Hereditary Ovarian Cancer Pedigree Studies, Part II Henry T. Lynch, Theresa Conway, and Jane Lynch

ABSTRACT: Hereditary ovarian carcinoma is heterogenous. There are at least three genetic variants, namely, hereditary site-specific ovarian carcinoma, hereditary breast~ovarian carcinoma syndrome, and Lynch syndrome II. Early age of onset characterizes these disorders. A crucial hallmark of these disorders is the integral association of extraovarian cancers, such as carcinoma of the endometrium and colon in Lynch syndrome II. We have described 24 pedigrees of ovarian cancer-prone families in order to depict the several differing heterogenous variants. Interest in hereditary ovarian cancer has increased remarkably, due in part to the fact that its surveillance has been wholly unsatisfactory, as have therapeutic measures. Prevention through prophylactic oophorectomy offers hope. However, there is a risk for extraovarian peritoneal serous papillary carcinoma, consonant with primary cancer of the ovary. This must be discussed with these at-risk patients. Until a biomarker of acceptable sensitivity and specificity is identified, the family history must remain the key to hereditary ovarian cancer diagnosis. INTRODUCTION During their lifetimes, 1 in 67 w o m e n in the United States will develop ovarian carcinoma. This disease will affect 20,700 w o m e n and cause the deaths of 12,500 during 1991 [1]. It has the highest mortality of all gynecologic malignancies. As far as we can determine, there is no one at greater risk for ovarian cancer than a patient who is in the direct genetic lineage of a hereditary ovarian cancer syndrome kindred and whose mother, sister, and/or daughter is affected with this disease and/or an integrally related syndrome cancer [2, 3]. Surveillance for ovarian carcinoma has been wholly unsatisfactory. Most patients already have stage III or IV disease when ovarian cancer is diagnosed. At the present time, therapeutic measures are woefully inadequate for patients who present with advanced disease [4]. Needed are measures for the identification of w o m e n who are at inordinately high risk for this disease so that they can be targeted for intensive research in the interest of developing cost effective, innovative screening measures for its early detection. Prevention through prophylactic oophorectomy could be provided to a selected subset of these high-risk women. Our purpose is to provide a series of pedigrees depicting a variety of cancer-prone families, inclusive of Lynch syndrome II, wherein ovarian cancer may be an integral lesion. Emphasis will be given to the need for a better u n d e r s t a n d i n g of the natural From the Departmentof PreventiveMedicine/PublicHealth, CreightonUniversitySchool of Medicine, Omaha, Nebraska. Address reprints requests to: Henry T. Lynch, M.D., Dept. of Preventive Medicine, Creighton University School of Medicine, California at 24th Street, Omaha, NE 68178. Support for this effort was provided by a grant from the National Cancer Institute, #1 R01 48802-02, from the Fraternal Order of Eagles, and the Council For Tobacco Research, Inc. #1297CR2. Received August 6, 1990; accepted September 24, 1990.

161 © 1991 ElsevierScience PublishingCo., Inc. 655 Avenueof the Americas,New York, NY 10010

Cancer GenetCytogenet52:161-183 (1991) 0165-4608/91/$03.50

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H T. Lynch et al. history, pattern of cancer distribution within families, and heterogeneity of hereditary ovarian cancer.

MATERIALS AND METHODS Study of our ovarian cancer-prone families has involved a search for cancer of all anatomic sites with verification of genealogic, medical, and cancer findings throughout the kindreds with the retrieval of primary medical and pathology documents [3]. Genealogic and medical data have been cross-referenced for accuracy through contact with key relatives in each of these families. Pedigrees (Figures 1-7) from our cancer family resource have been selected in order to depict an array of clinical settings involving putative hereditary ovarian cancer, consonant with its genetic heterogeneity. We present these families in order to illustrate the following: 1) that ovarian cancer may aggregate in certain families due to postulated primary genetic factors. However, it may be difficult to exclude chance; 2) that ovarian cancer may be integrally associated with other forms of cancer, such as carcinoma of the breast, (hereditary breast/ovarian cancer syndrome) or colon and endometrium (Lynch syndrome II); and 3) that certain of the natural history features of cancer genetics, such as early age of onset and an excess of multiple primary cancer may occur. RESULTS Figure 1 Family 2068 depicts the tumor combinations of endometrial (II-6, III-13), ovarian (II-6, III-10, III-13), and colon carcinomas (II-3, II-6). This association of gynecologic cancer with nonpolyposis colorectal cancer (CRC) is consistent with the Lynch II syndrome. Family 956 shows the tumor combinations of endometrial and ovarian carcinoma, with an absence of colon cancer. Four occurrences of endometrial carcinoma are noted (I-3, I-4, II-6, II-8) involving two affected sisters in each generation. The proband (II-9) had carcinoma of the breast and her sister (II-3) had carcinoma of the ovary, and she subsequently developed a lymphoma. Family 1933 is a Lynch syndrome II kindred showing features that suggest an integral association with carcinoma of the breast. In this family, a patient (IV-7) had extremely early onset of CRC at age 22, followed a decade later by carcinoma of the breast. Early onset carcinoma of the ovary at age 33 was also found in a direct-line relative (IV-13) whose father had CRC at age 36 (III-19). In another branch of the family, three occurrences of breast cancer were identified. Specifically, a mother (II-1) had late onset breast cancer at age 76, followed by CRC at age 80 and gastric cancer at age 83. This w o m a n had two daughters (IIIol, III-2) with breast cancer at ages 48 and 53, respectively. Figure 2 Family 3103, although exhibiting features of Lynch syndrome II, has been tentatively classified as the hereditary breast/ovarian carcinoma syndrome. The association of ovarian and endometrial carcinoma (III-2) with CRC (II-1, IV-20) is noted. Of interest is the fact that the proband's mother (II-1) and five of her maternal aunts (II-3, II-4, II-5, II-6, II-7) manifested breast cancer. Among these women, individual II-3 had a daughter (IIIo4) who manifested breast cancer at the age of 66 and a second daughter (IIIo5)with ovarian carcinoma at the age of 43. This woman (III-5) had two daughters (IV-7, IV-8) with breast cancer at the ages of 36 and 30.

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Family 3076 is also a putative hereditary breast/ovarian cancer kindred. There is inferred paternal transmission of cancer through a progenitor (I-2) who had canceraffected daughters through two marriages. In the first marriage, a daughter (II-1) had Both breast and ovarian carcinoma, a second daughter (II-3) had ovarian carcinoma, and a third daughter (II-5) had breast cancer. In the second marriage, a daughter (II-7) had bilateral breast cancer. Individual II-5 had three daughters (III-lO, III-11, III-13) with carcinoma of the breast. Individual II-1, who had been affected with breast and ovarian carcinoma, had three daughters with cancer; one (III-1) with ovarian carcinoma, the second with abdominal carcinoma, primary site undetermined, and the third daughter (III-6) manifested CRC 4 years following a prophylactic hysterectomy and bilateral salpingo oophorectomy (TAHBSO). Family 2619 depicts four sisters (II-5, II-7, II-8, II-13) with ovarian cancer. A fifth sister in this sibship (II-9) had carcinoma of the breast. The daughter (III-6) of one of the ovarian cancer-affected patients (II-7) manifested CRC only five months following TAHBSO. There are certain similarities between family 2619 and family 3076, mentioned above.

Figure 3 The pedigrees in Figure 3 show occasional patients with CRC. However, we cannot exclude chance as an explanation for these CRC occurrences. Family 2770 shows three siblings with CRC (II-2, II-3, II-6). Note, however, that only one of these patients (II-6) is a presumptive obligate gene carrier for carcinoma of the breast and ovary in that he was the progenitor of a sibship wherein five of his daughters (III-12, III-14, III-17, III-20, III-22) manifested these tumors. Four of his granddaughters in the direct genetic lineage (IV-6, IV-8, IV-11, IV-21) had also manifested premenopausal breast cancer. Family 2850 has some similarities with family 2770. Note again that the progenitor (II-3) manifested CRC, and he had progeny with cancer through two separate marriages. The predominant findings in this kindred are consonant with the hereditary breast/ovarian carcinoma syndrome. However, we also note that one of the progenitor's granddaughters (IV-14) had breast cancer and CRC. Ovarian cancer has occurred in two patients (V-2, V-12), with one of these women (V-2) having ovarian cancer as a second primary in combination with breast cancer.

Figure 4 Figure 4 shows three kindreds (families 1704, 133, and 2223) that illustrate features suggestive of so-called site-specific hereditary ovarian carcinoma. Note the predominance of carcinoma of the ovary and the relative paucity of other cancer types in each of these kindreds. In family 1704, five women in three generations are affected with ovarian cancer (I-1, II-2, II-3, II-6, III-3). Two patients (I-4 and II-1) had CRC, while a single patient (III-11) had carcinoma of the breast. Family 133 depicts four occurrences of ovarian carcinoma. This has involved identical twin sisters in generation II (II-1, II-2) and two sisters in generation III (III-1, III-3). Breast cancer has not occurred in this family. In family 2223, there are seven verified occurrences of ovarian carcinoma in generations III and IV. Three occurrences of breast cancer in the direct lineage (III-3, III-5, III-10) are also noted.

Figures 5 a n d 6 Families that display more typical findings of the hereditary breast/ovarian carcinoma syndrome are illustrated in Figures 5 and 6. In Figure 5, Family #1234 is striking in that we have nine women through four generations with ovarian carcinoma (I-2, II-2,

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H.T. Lynch et al. II-8, III-1, III-6, III-9, III-20, III-23, IV-l). Seven patients had carcinoma of the breast (I-2, III-17, III-19, III-21, IV-l, IV-13, IV-18). The proband in this kindred (IV-l) had breast and ovarian carcinoma. Her son (V-l) had Wilms' tumor, the significance of which remains elusive. In Figure 5, family 2944 shows ovarian carcinoma to have occurred in two generations. At the time of the initial family study, individual III-5 had bilateral breast cancer at the ages of 30 and 33. Her mother (II-2) was cancer-free. However, she was considered to be an obligate gene carrier by virtue of her position in the pedigree. Her most recent breast evaluation disclosed carcinoma of the breast at age 53. In family 2651 (Fig. 6), the proband (III-1) had ovarian carcinoma at age 55. Her daughter (IV°l) had breast cancer at age 32. The proband's three sisters (III-5, III-6, III-7) all had breast cancer, with one of these sisters (III-6) experiencing an ovarian carcinoma as a separate primary. Of interest is the proband's maternal aunt (II-7) who had breast cancer. This lady had a granddaughter (IV-18) who, on a routine physical examination prior to oral surgery, was found to have a palpable right ovarian mass lesion. Exploratory laparotomy showed early stage pseudomucinous cystadenocarcinoma of the right ovary. In family 3102 (Fig. 6), the proband (III-1) presented with concern about her cancer risk. Her mother (II-1) had breast cancer, as did two of her mother's sisters (II-3, II-7). Another of these sisters (II-6) had ovarian carcinoma. This woman had a daughter (III-lO) with early onset breast cancer. The sister (II-3) with breast cancer had a daughter (III-8)with both breast and ovarian carcinoma.

Figure 7 Figure 7 depicts pedigrees of four families (families 2742, 2778, 3052, and 3077) who show predominant breast cancer. However, in each of the kindreds, there is a single case of ovarian carcinoma. In family 3052, we note a patient (III-5) with ovarian carcinoma who is a putative obligate gene carrier by virtue of the fact that her daughter (IV-9) had remarkably early onset (age 31) carcinoma of the breast. We see a similar p h e n o m e n o n in family 2742 in patient III-2 with ovarian carcinoma, who has two daughters (IV-l, IV-2) with early onset carcinoma of the breast. DISCUSSION The etiologic role of hereditary factors in ovarian cancer has been extensively reviewed [2, 3]. Significant ovarian cancer excess has been observed in context with at least three hereditary ovarian cancer-prone syndromes: 1) hereditary site-specific ovarian carcinoma syndrome [5]; 2) hereditary breast/ovarian cancer syndrome [2, 6, 7]; and 3) Lynch syndrome [I [8]. Less well known is the Peutz-Jegher's syndrome [9-11], wherein sex cord tumors with annular tubules have been shown to be integral lesions. Ovarian fibromas and cysts have been found to aggregate in families on a sitespecific basis [12] and to be accompanying lesions in the multiple nevoid basal cell carcinoma syndrome [13-16]. The heterogeneity observed in ovarian cancer is comparable to the heterogeneity encountered in genetic studies of carcinoma of the breast [2, 5, 17] and colon [18-20]. Schildkraut et al. [21] examined the genetic relationship between carcinoma of the ovary, breast, and endometrium in a population-based case/control study. Relatives of breast cancer probands had a higher relative risk for both breast and ovarian cancer, but not for carcinoma of the endometrium. These investigators concluded that their data was in support of the existence of a familial breast/ovarian cancer syndrome and that carcinoma of the endometrium, while heritable, appeared to be genetically unrelated to cancers of the breast and ovary.

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These observations, in enunciating the heterogeneity of hereditary ovarian cancer, clearly mandate the necessity for ascertaining cancer of all anatomic sites in family studies for accuracy in hereditary cancer syndrome diagnosis. Knowledge of this heterogeneity is equally vital to targeting surveillance/management strategies in these high risk kindreds. One must therefore extend screening to specific extraovarian sites such as the breast in the hereditary breast/ovarian carcinoma syndrome [6, 17] or endometrium and colon in Lynch syndrome II [18]. Until a biomarker(s) of acceptable sensitivity and specificity to the ovarian cancer-prone genotype(s) is developed, a well-orchestrated family history remains the only method available for identifying hereditary ovarian cancer proneness. Knowledge of ovarian cancer genetics provides a powerful potential for improving control strategies for this disease. Our series of pedigrees (Figs. 1-7) indicates a precision in risk factor assessment that exceeds that for any known risk for ovarian cancer. Unfortunately, the evaluation of families may be hampered by their small size, differences in sex ratio (such as an excess of males and thereby a limited number of women who would be at risk for ovarian carcinoma), limited patient or physician cooperation, death of key relatives at an early age prior to expression of cancer phenotype, or lack of pathology verification of a cancer which may have been a primary lesion of the ovary but had been misclassified. For example, in family 2979, Figure 5, our current pathology review of the reported omental carcinoma from patient I-2 revealed serous papillary carcinoma, most likely of ovarian origin. Many other limitations to family studies may obfuscate hereditary cancer syndrome diagnosis. However, the importance of identifying high risk genetic groups, particularly with the intent of elucidating etiology, pathogenesis, and improving cancer control, has become a pervasive research and clinical objective. The recent observation that ovarian cancer aggregates in a genetically meaningful manner in certain families has provided an impetus to this hereditary cancer research [2]. This interest has also been promulgated by deaths from ovarian cancer among young public figures. As a result, many women are indiscriminately calling for removal of their ovaries as a form of protection from this disease. Unfortunately, some physicians are obliging in an equally indiscriminating manner, without giving prudent attention to the woman's psychological condition, age, or risk status. In certain circumstances, familial ovarian cancer risk is erroneously overestimated, as evidenced in such statements as, "If you have two relatives affected with ovarian cancer, your risk is enormous and you could benefit from prophylactic oophorectomy."

Clinicogenetic Significance of Pedigrees We have attempted to describe various nuances of ovarian cancer's heterogeneity through a series of pedigrees (Figs. 1-7). These families provide a panorama of clinicogenetic examples wherein ovarian carcinoma has been an apparently integral lesion. We have identified families, such as family 2068 in Figure 1, which show features consonant with Lynch syndrome II. The proband's mother (II-6) had the cardinal features of this disorder, namely, carcinoma of the ovary and endometrium at age 46 and colon cancer at age 47. She developed metachronous colon cancer at age 56. The daughter of the above patient (III-13) had ovarian and endometrial carcinoma at age 38. The family is also of particular interest because of the occurrence of cancer of the ureter (III-9) at age 49, and renal cell carcinoma (III-12) at age 64. Urological cancer may be an integral lesion in Lynch syndrome II [20]. Other families, such as families 956 (Fig. 1), 3103 (Fig. 2) and 1704 (Fig. 4) show features of Lynch syndrome II,

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which are less convincing but nevertheless may, given further prospective study, be found to fulfill this diagnosis. Ovarian cancer occurs with significantly less frequency than its endometrial carcinoma counterpart in Lynch s y n d r o m e II. The same situation exists in the hereditary breast/ovarian cancer s y n d r o m e where breast cancer is mor~ common. Nevertheless. we have identified many circumstances wherein ovarian carcinoma is believed to be an integral lesion in these disorders by virtue of the patient's position in the pedigree as a putative obligate gene carrier (Fig. 2, family 3103, III-5; Fig. 6, family 2651, III-l: Fig. 6, family 3102, II-6; Fig. 7, family 3052, III-5) and/or where the disease has occurred as a second primary in the combination of breast and ovarian carcinoma (Fig. 3, family 2770, III-12; Fig. 3, family 2850, IV-l; Fig. 5, family 1234, IV-l; Fig. 5, family 1879, III-1, III-3; Fig. 6, family 2651, III-6; Fig. 6, family 3102, III-8). Hereditary site-specific endometrial carcinoma, as far as we can determine, has not been recognized as a distinct hereditary cancer syndrome [2]. In one of our families (Fig. 1,956), e n d o m e t r i a l carcinoma affected four patients (two pair of sisters in two generations). The cancer pattern in the family is not sufficient to establish a hereditary cancer s y n d r o m e diagnosis, and the absence of colon cancer in this family makes it difficult to establish a Lynch s y n d r o m e II diagnosis. However, it must be e m p h a s i z e d that h e r e d i t a r y cancer s y n d r o m e diagnosis may be exceedingly difficult when based on a limited n u m b e r of genetically at-risk individuals. Prospective study of this family, and others like it, m a y enable elucidation of its diagnosis. Nevertheless, chance m u s t also be considered as an explanation for such cancer aggregations. Similar problems are encountered when considering the diagnosis of hereditary site-specific ovarian carcinoma, as has been illustrated by the three kindreds in Fig. 4 (families 1704, 2223, and 133). In one of these families (1704), two patients (I-4, II-1) had CRC. However, this is not sufficient to enable confidence that we are dealing with Lynch s y n d r o m e II. In family 2223, seven occurrences of ovarian cancer have been verified. However, we also note three occurrences of breast cancer, two of w h i c h are early age, in w o m e n in the direct genetic lineage (III-3, III-5, III-10). Are these breast cancer occurrences due to chance or are they integral to the kindred? F a m i l y 133 is a relatively small kindred and it would seem prudent that we consider the p o s s i b i l i t y that over time, this may evolve into a hereditary breast/ovarian cancer syndrome. Given the frequent association of these tumors in the hereditary setting, we therefore r e c o m m e n d that high-risk w o m e n in families of this type undergo rigorous breast cancer surveillance even though we have not yet identified breast cancer as an integral tumor in the kindred. There has been considerably more experience with the hereditary breast/ovarian carcinoma s y n d r o m e (Figs. 5 and 6) [2, 6, 7]. This association is evident especially in family 1234 (Fig. 5). Occurrences of either breast or ovarian carcinoma in i n d i v i d u a l s c o n s i d e r e d as obligate gene carriers by virtue of their position in the pedigree lend confidence to this hereditary cancer s y n d r o m e diagnosis for this k i n d r e d (I-2, II-2, III-1, III-9). Paternal T r a n s m i s s i o n of Ovarian Carcinoma

M o u n t i n g evidence indicates that the hereditary variant of ovarian carcinoma is inherited as an autosomal d o m i n a n t trait. In such hereditary settings, mother-todaughter transmission of cancer may be readily identifiable. However, the significance of male transmission may be missed because insufficient attention has heretofore been given to the importance of pursuing the paternal lineage w h e n considering hereditary risk factors for ovarian carcinoma. In families with sex-limited tumors such as h e r e d i t a r y site-specific ovarian carcinoma and the breast/ovarian carcinoma syndrome, males, who may be obligate gene carriers, are often difficult to identify,

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yet they may transmit the cancer syndrome-associated gene to half of their daughters and sons. In contrast to these disorders, in Lynch syndrome II, males as well as females who are obligate gene carriers are easier to identify because they wilt often manifest the non-sex-limited syndrome cancer(s). They transmit the cancer-prone gene to half of their daughters as well as to half of their sons. Their daughters will then be at high risk for carcinoma of the ovary, endometrium, and colon. Figure 5, family 1234, depicts paternal transmission (II-10) in a breast/ovarian cancer-prone kindred. Figure 3, family 2770 (II-6) and family 2850 (II-3, IV-10) also depict paternal transmission.

Identical Twins The gentleman (IV-10 in Fig. 3, family 2850, referred to above) had an unaffected daughter (V-13), whose identical twin sister (V-12) was diagnosed with ovarian carcinoma. This unaffected daughter's cancer risk approaches 100%. Ovarian carcinoma in identical twin sisters is noted in family 133, Figure 4 (II-1, II-2). Remarkably, one of the identical twins (II-1) had two daughters (III-1, III-3) with verified ovarian carcinoma. This is an example of a hereditary cancer syndrome setting where one would expect to encounter concordance for cancer among monozygous twins.

Age at Ovarian Cancer Onset Age of ovarian cancer diagnosis was studied in the site-specific hereditary ovarian cancer syndrome, the breast/ovarian cancer syndrome, and Lynch syndrome II (Lynch et al., submitted). Age of onset in each of the three disorders was significantly (p 0.001) earlier than the general population mean of 59. There were also significant differences in age of onset (p = 0.050) among these three cohorts. The mean age of ovarian diagnosis in the breast/ovarian cancer cases was nearly 7 years below the general population mean of 59; the mean in the site-specific ovarian cancer cases was 10 years below the general population mean; and the mean in the Lynch syndrome II cases was 14 years below the general population mean. A statistical test (one-way analysis of variance) to determine whether the three sets of ages differed significantly showed the test to be significant, although barely so ( p = 0.050), indicating that there may be clinically significant differences between these three cohorts in the age of onset component of ovarian cancer. Ovarian cancer histology in these heterogeneous subsets was similar to that of patients with negative family histories. Our findings indicate that there may be clinically significant heterogeneity in age at diagnosis of ovarian cancer among these ovarian cancer-prone syndromes. This has important implications for understanding ovarian cancer's natural history and for targeting surveillance/management strategies.

Extraovarian Peritoneal Serous Papillary Carcinoma An important clinical consideration pertains to recent reports of peritoneal carcinomatosis following prophylactic oophorectomy among ovarian cancer-prone patients [22-24]. The problem of extraovarian peritoneal serous papillary carcinoma is becoming a more commonly recognized clinicopathologic entity. Indeed, in one series, 31 of 236 (13%) patients with an initial diagnosis of invasive serous ovarian carcinoma fulfilled the surgicopathologic criteria for this disorder. Unfortunately, in this series, family histories were not obtained [25]. Because of the possibility that a fraction of patients undergoing prophylactic oophorectomy as a result of their increased cancer genetic risk may subsequently

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H.T. Lynch et al. manifest this entity, it is extremely important that the risk for this complication be discussed prior to surgery.

Biomarkers and Ovarian Carcinoma Molecular genetic and cytogenetic studies of ovarian cancer have received only limited attention. No single etiologic factor and/or biomarker has been consistently linked to ovarian cancer's susceptibility. The expression of c-erb-B2 (neu) may correlate with prognosis of ovarian cancer [26]. Ki-ras and m y c amplification and overexpression have been described in ovarian cancer [27-30], as has been allele loss at the Ha-ras locus [31]. Research in this area commands the highest possible priority. Cytogenetic studies have shown occasional genetic alterations that may be etiologically important in ovarian cancer [32]. Ovarian carcinoma cell lines have revealed structural abnormalities most consistently involving chromosomes 1, 3, and 6 [27, 33-35].

Alpha-L-Fucosidase Lynch et al [36] studied alpha-L-fucosidase (ALF) activities in plasma samples from three ovarian cancer-prone families. A significant inverse correlation of cancer susceptibility and enzyme activity was observed in these families. Because a low level of plasma ALF activity is an inherited characteristic that has been termed the "fucosidase variant," these findings provoked interest in the fucosidase variant relative to genetic transmission of susceptibility to ovarian cancer. In a subsequent study of these same plasma samples, Wells et al. [37] observed that the concentrations of lipid-associated sialic acid (LAS) was also inversely correlated with the ALF activities, and therefore, directly correlated with cancer susceptibility in these families.

CA-125 The most extensively studied serum marker in non-mucinous epithelial ovarian cancer has been CA-125. This marker has been shown to be elevated in 82% of patients with histologically confirmed ovarian cancer when compared to only 1% in healthy female controls [38]. Unfortunately, CA-125 has not been found to be useful in detecting Stage I and II ovarian cancer. Its lack of specificity has resulted from the fact that elevations of CA-125 have been reported in patients with endometriosis and other benign inflammatory conditions of the pelvis [39]. In collaboration with Robert Bast, MD, we have had two interesting anecdotal experiences with the use of CA-125 in breast/ovarian cancer-prone families. The proband (IV-l) in family 1234, Figure 5, manifested breast cancer and was considered to be an obligate gene carrier. Thereby, she was considered to have an approximate 100% lifetime risk for ovarian cancer. A baseline serum CA-125 was 2421.3/~/mL. The patient underwent prophylactic total hysterectomy and bilateral salpingo oophorectomy (TAHBSO), at which time an ovarian mass lesion was observed, with a diagnosis of "borderline ovarian carcinoma." She was lymph node-negative. The CA-125 dropped to 4.6/~/mL 5 weeks following surgery. Repeat CA-125 in this patient remains at normal levels (< 5.0/z/mL). A woman from a separate hereditary breast/ovarian cancer-prone kindred also manifested carcinoma of the breast and was thereby considered to be an obligate gene carrier. Her baseline CA-125 was 41.9 /z/mL. Three months later, it rose to 69.8. TAHBSO was performed and the findings were histologically normal for both ovaries. Four months after surgery, the CA-125 returned to a normal (7.0/~/mL) level. Was this an example of a precancerous ovary that was histologically "normal" given the

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limitations of the microscopic evaluation employed? Were there microscopic foci of cancer in one of these ovaries that were undetectable by us?

Genetic Counseling of High-Risk Patients Genetic counseling in any form of hereditary cancer should ideally be performed by the family physician. This can then be reinforced by the medical oncologist, gynecologist, or, when necessary, the cancer geneticist. Genetic counseling should provide the patient, and ideally his/her high-risk relatives, with information about genetic risk, as well as the natural history of the particular hereditary cancer syndrome. Physicians must devise better methods for cost containment in the management of families at high risk for ovarian cancer. We have found that meeting together with as many as 10 or 15 members from a cancer-prone family is an extremely cost-effective measure. These informational and group therapy-oriented genetic counseling sessions enable a freewheeling question/answer educational experience for these at-risk patients. A trained nurse, working closely with the physician, can be a valuable aid to this process. In these sessions, particular attention should be given to a description of the natural history of the specific form of hereditary cancer, its distribution within the family, and its mode of genetic transmission. It is important that risk estimates be accurate. Over- or underestimating risk assessment should be avoided. Psychosocial counseling should be provided. An empathetic "listening ear" will allow the patients to cast their "family crisis problem" into an objective perspective. These group sessions extend the expertise of the nurse and physician in a manner that may equal or even exceed that which can be provided on a one-to-one basis. In addition, the accrual of cancer family history data may be enhanced because the family members are able to utilize each other as informational resources. Hence, the pooled knowledge about affected and unaffected family members can be assessed and its accuracy increased through this process. We have utilized this approach for more than two decades and have found it to be effective. Hopefully, the counseling will enhance knowledge and increase compliance with the recommended surveillance and management programs for hereditary proneness to cancer. SUMMARY AND CONCLUSIONS In conclusion, our pedigree findings indicate the need to understand the natural history and heterogeneity of ovarian cancer for purposes of establishing hereditary cancer syndrome diagnoses. This should then enable the recognition of patients who are at increased risk for this disease and/or hereditary syndrome integrally-related forms of cancer; i.e., breast cancer in the hereditary breast/ovarian cancer syndrome, or carcinoma of the colon and endometrium in Lynch syndrome II. With this knowledge, appropriate organ-targeted surveillance and management programs can be enacted.

ADDENDUM Since this paper was accepted, we have discovered genetic linkage, in collaboration with Drs. G. Lenoir, S. Narod, and J. Feunteun of the Unit of Mechanisms of Carcinogenesis, Centre International de Recherche sur le Cancer in Lyon, France, and with Patrice Watson, PhD, Theresa Conway, BSN, and Jane Lynch, BSN from our Department of Preventive Medicine. Co-segregation of cancer susceptibility was sought with a specific allele of a polymorphic system that has been mapped to a known chromosomal location. Over 60 polymorphic DNA markers distributed throughout the genome were analyzed. With the probe CMM86, the maximum lod score for our

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largest family (1816) was 2.72 at O = 0.07. Of the remaining four families, two showed evidence of linkage with this probe and two appeared to be unlinked. The m a x i m u m lod score for all five families, assuming heterogeneity, was of 3.03 at O = 0.10. Our data strongly support the identification of a breast cancer susceptibility locus on chromosome 17q12-p23 and are consistent with heterogeneity in hereditary breast cancer (HBC). Of keen interest is the fact that this is the identical chromosomal susceptibility that was identified in familial early onset breast cancer (lod score 5.98) by Hall et al. 4° We anticipate further progress in molecular/genetic and gene linkage studies in cancer-prone families, thereby making it crucial that oncologists and family physicians become prepared for the application of this knowledge to the clinical practice setting. Dissemination of this linkage information must be done with great care. Certain patients may not want to know of their cancer susceptibility status: others may d e m a n d this information. However, this knowledge may have serious ramifications from the standpoint of health care insurance providers. They may wish to rate patients, or even deny them policies, if they are aware that the patients are linkage positive, and thereby at markedly increased cancer risk. In spite of these concerns, this genetic marker information may be used advantageously in HBC by heightened surveillance and, in certain situations, surgical prophylaxis. REFERENCES 1. Boring CC, Squires TS, Tong T (1991): Cancer statistics, 1991. Ca 41:19-36. 2. Lynch HT, Kullander S (1987): Cancer Genetics in Women. CRC Press, Boca Raton. 3. Lynch HT, Fitzsimmons ML, Conway T, Bewtra C, Lynch JF (1990): Hereditary carcinoma of the ovary and associated cancers: a study of two families. Gyn Onc 36:48-55. 4. Piver MS (1987): Ovarian Malignancies: Diagnostic and Therapeutic Advances. ChurchillLivingstone, Edinburgh. 5. Lynch HT, Albano WA, Lynch JF, Lynch PM, Campbell A (1982): Surveillance and management of patients at high genetic risk for ovarian carcinoma, Ob Gyn 59:589-596. 6. Lynch HT, Harris RE, Guirgis HA, Maloney K, Carmody L, Lynch JF (1978): Familial association breast/ovarian cancer. Cancer 41:1543-1548. 7. Lynch HT, Krush AJ, Lemon HM, Kaplan AR, Condit PT, Bottomley RH (1972): Tumor variations in families with breast cancer. JAMA 222:1631-1635. 8. Lynch HT, Lynch PM (1979): Tumor variation in the Cancer Family Syndrome: ovarian cancer. Am J Surg 138:439-442. 9. Riley E, Swift M (19801: A family with Peutz-Jegher syndrome and bilateral breast cancer. Cancer 46:815. 10. Rodu B, Martinez MG Jr (19841: Peutz-Jegher's syndrome and cancer. Oral Surg Oral Med Oral Path 58:584-588. 11. Scully RE (1988): Juvenile granulosa cell tumor. Ped Path 8:423-427. 12. Dumont-Herskowitz RA, Safaii HS, Senior B (1978): Ovarian fibromata in four successive generations. J Pediatr 93:621-624. 13. Gorlin RJ (1987): Nevoid basal-cell carcinoma syndrome. Medicine 66:98-113. 14. Johnson AD, Hebert AA, Esterly NB (1986): Nevoid basal cell carcinoma syndrome: bilateral ovarian fibromas in a 3-½ year old girl. JAAD 14:371-374. 15. Lynch HT, Fusaro RM (1982): Cancer-Associated Genodermatoses. VN Reinhold Co., New York. 16. Springate JE (1986): The nevoid basal cell carcinoma syndrome. J Ped Surg 21:908-910. 17. Lynch HT (1981): Genetics and Breast Cancer. VN Reinhold Co., New York. 18. Lynch PM, Lynch HT (1985): Colon Cancer Genetics. VN Reinhold Co., New York. 19. Lynch HT, Kimberling WJ, Albano WA, Lynch JF, Biscone K, Schuelke GS, Sandberg AA, Lipkin M, Deschner EE, Mikol YB, Elston RC, Bailey-WilsonJE, Danes BS (1985): Hereditary nonpolyposis colorectal cancer, Parts I and II. Cancer 56:939-951.

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