Excess of Rare Cancers in Werner Syndrome (Adult Progeria)

Vol. 5. 239-246, April 1996 Cancer Epidemiology, Biomarkers & Prevention 239

Makoto Goto, Robert W. Miller,’ Yuichi Ishikawa, and Introduction Haruo Sugano2 WRN,3 an autosomal recessive trait (MIM#27770) character- Department of Rheumatic Diseases, Tokyo Metropolitan Otsuka Hospital. ized by features of premature aging, is unusually frequent in 2-8-I, Minami-Otsuka, Toshima-ku. Tokyo 170, Japan IM. 0.1: Genetic Japan because of previously high rates of inbreeding there. Epidemiology Branch. National Cancer Institute, Bethesda, Maryland 20892- Death on average is at 47 years, due primarily to arterioscle- 7360 IR. W. M.J: and Cancer Institute, Kami-Ikebukero, 1-37-1, rosis, diabetes mellitus, or cancer ). The gene has been Toshima-ku. Tokyo 170. Japan IY. I.. H. S.I (I mapped to chromosome 8pl 1 . 1-21 . 1 in both Japanese and Caucasians (2, 3). Since 1940, WRN has been associated with an excess of Abstract cancer of unusual types, especially sarcomas ( 1). The most The association between genetic disorders and diverse recent review of the literature outside Japan was by Salk (4) 13 cancers has provided clues for laboratory research into years ago, and there have been two partial reviews of the carcinogenesis. Such an opportunity now arises from Japanese literature (5, 6). Japanese interest in WRN has led to studies of cancer in Werner syndrome (WRN). Soft-tissue case reports of neoplasia in 124 patients (82 since 1985), as sarcoma (STS) and benign meningioma have been compared with 34 outside Japan (4 since 1985). Many of the associated with WRN, an autosomal recessive disorder Japanese case reports are in journals not available in the rest of characterized by premature aging, more commonly the world. Reported here is the remarkable array of neoplasms reported in Japan than elsewhere, in part because of revealed by the Japanese literature as compared with case inbreeding. In the literature we found 124 case-reports of reports from other countries. Similar case series in the past have neoplasia and WRN from Japan and 34 from outside determined the array of cancers in genetic syndromes, which Japan, 1939-August 1995. They reveal a greater diversity led laboratory investigation to the first recognition, for exam- of neoplasia in WRN than was previously known. In pie, of tumor suppressor genes (7, 8), and germline mutations Japanese, there were 127 cancers, 14 benign meningioma, of the p53 gene (9). and 5 myeloid disorders, as compared with 30, 7 and 2 respectively in non-Japanese. The ratio of epithelial to Materials and Methods non-epithelial cancers was about 1 : 1 for Japanese and for In Japan, the literature has been searched for publications on non-Japanese instead of the usual 10:1. Both series had WRN through a citation index (Igaku-Chuo-Zasshi, 1960- excesses of STS, osteosarcoma, myeloid disorders, and 1986) and its continuation as a computer index since 1987. For benign meningioma. In addition, the Japanese had an cases outside Japan, searches were made by computer (Medline excess of thyroid cancer (20 versus 2 cases in non- and Cancerlit) since 1966. Bibliographies of each report since Japanese) and melanoma (21 versus 3 cases), including 5 1939 were examined for additional references. Care was intranasal and 13 of the feet. STS, osteosarcoma, taken to exclude multiple reports of the same patient, rec- melanoma, and thyroid carcinoma accounted for 57% of ognized by details of family and personal histories and all cancer in WRN as compared with 2% expected based demographic characteristics. on the Osaka population at 25-64 years of age. Multiple Diagnosis of WRN was based on the presence of 3 of 4 tumors were reported in 19 Japanese and 5 non- criteria under age 35: unusual body habitus (short stature and Japanese. In Japan, nine first-degree relatives had WRN stocky trunk with spindly limbs), premature senescence (gray and cancer, six of whom were concordant as to site and/ hair, cataracts, osteoporosis, and arteriosclerosis), scleroderma- or cell type. The WRN gene has been mapped to like skin changes, and endocrine disorders (diabetes mellitus or chromosome 8p The high frequency of thyroid cancer hypogonadism; Ref. 10). Diagnosis of neoplasia was as given and melanoma in Japanese, not found in Caucasians, may by the original authors. Although WRN occurs throughout the be related to a report of linkage disequilibrium with the world, it has been reported with neoplasia only in Japanese and WRN gene in Japanese but not in Caucasians and to Caucasians, except for one United States black. Seven diag- haplotype differences within and between the two races, noses in Japanese that were given as “cancer” were counted as suggesting multiple independent mutations. carcinoma because of its marked predominance in the organs involved (one each of stomach, nasal cavity, esophagus, pan- creas, uterus, ovary, and skin) and to give a conservative ratio of non-epithelial to epithelial cancer without affecting other

Received 10/26/95; revised 1/8/96: accepted 1/9/96. conclusions. Two benign brain tumors in Japanese are not The costs of publication of this article were defrayed in part by the payment of included in the totals, but are used for the ratio of meningioma page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

I To whom requests for reprints should be addressed, at Genetic Epidemiology Branch, EPN-400, National Cancer Institute, Bethesda, MD 20892-7360. 3 The abbreviations used are: WRN. Wemer syndrome: MDS, myelodysplastic

2 This binational collaboration developed from a workshop on cancer clusters syndrome; AML. acute myelogenous leukemia; ALM. acral lentiginous mela- held by the U.S-Japan Collaborative Cancer Research Program in March 1994. noma; LFS, Li-Fraumeni syndrome.

to other brain tumors, to allow comparison with published as compared with 5 in non-Japanese. The most notable were series. four biliary cancers [two intrahepatic (120, 121), one extrahe- Publishing on cancer in WRN is easier in Japan than patic (122), and one gall bladder (123)] in Japan, and one elsewhere because of space available in a substantial number of extrahepatic bile-duct carcinoma in the United States (77). small, specialized, or local journals. The case reports in Japan There were no reports of lymphoma or colorectal carcinoma, were ascertained through a national citation index, whereas and only one case each of pulmonary, pancreatic, esophageal, those from outside Japan were ascertained from international and prostatic carcinoma (Table 1). Overall, the Japanese had indices that do not cover most of the Japanese reports cited substantially higher frequencies than non-Japanese of thyroid here. The cases in Japan were thus more fully ascertained than carcinoma, melanoma, and the category “other carcinoma.” were the cases outside Japan. The interpretation of the data Neoplasia was diagnosed in WRN between 25 and 64 depends on the distribution by cell type for each case series as years of age, except for a Japanese with osteosarcoma at 20 compared with one another and with the general population. years4 and a Canadian with AML at 24 years (94). There were no substantial differences in age distribution according to tumor type. In this age range, four rare cancers (soft-tissue sarcoma, Results osteosarcoma, melanoma, and thyroid cancer) accounted for The 34 non-Japanese cases of WRN with cancer occurred in the 57% of all cancer in Japanese with WRN as compared with 2% United States (13 cases), Canada (2 cases), Sardinia (5 cases), in the general population of Osaka (143). elsewhere in western Europe ( I 3 cases) and Turkey ( 1 case). Nineteen Japanese with WRN and 5 non-Japanese had Consanguineous parentage was reported in 56 of 80 Japanese multiple primary neoplasms, or neoplasia with MDS or myelo- cases (70%) for whom this information was published, and in fibrosis (Table 2). The frequency of multiple primary neoplasia 14 of 30 cases (47%) outside Japan. was the same (15%) in both series, but among the Japanese, The 124 Japanese cases occurred throughout the nation. thyroid carcinoma occurred in 10 cases (cases 1-9 and 1 1), a They had 127 cancers, 14 benign meningiomas, and 5 cases of neoplasm to which Caucasians with WRN were not prone. MDS and/or myelofibrosis. In the series outside Japan there Meningioma occurred in 5 Japanese (cases 8 -1 2), one of whom were 30 cancers, 7 benign meningiomas, and I case each of developed MDS (67) and another of whom developed myelo- MDS and myelofibrosis; 19 Japanese and 5 Caucasians had fibrosis (68) after removal of the meningioma (cases I 1 and more than one of these diagnoses. 12). Three Caucasians also had meningioma and another neo- Thyroid carcinoma accounted for 14% of neoplasia in plasm (cases 3’-S’). Japanese with WRN as compared with 3% in non-Japanese. In Japan, nine first-degree relatives with cancer and WRN When benign meningioma and preleukemic disorders were have been reported (Table 3), six of whom were concordant excluded, the ratio of epithelial to non-epithelial cancer was I: 1 with the index patient as to the site and/or type of cancer and in Japanese and non-Japanese (Table 1 ), as compared with 10:1 were of similar age (families 1-6). Two sisters had intranasal in the general adult population (1 1). Soft-tissue sarcomas, 23 in melanoma (46), two brothers had fibrosarcoma of the leg (5), Japan and 7 elsewhere, were of diverse cell types; 8 cases of and a trio of siblings had soft-tissue sarcoma at the elbow (two osteosarcoma were reported in Japan and 4 elsewhere. The malignant fibrous histiocytoma and one leiomyosarcoma; Ref. anatomic site of osteosarcoma was unusual in three cases: the I 9). In only one Caucasian sibship were two members affected, patella in a Japanese (38) and the small bones of the feet (29) with neoplasms of discordant type. Genotype/phenotype corre- and orbit (45) in Caucasians. lations in the Japanese may be due to a mutation that induces a Melanoma is rare in Japanese, but not among those with site-specific cancer or to host-susceptibility factors, either ge- WRN. The distribution by site among the 21 cases was unusual: netic or environmental. 13 were of the feet (23, 49, 52-61 ), 5 were intranasal (46-49), and I was esophageal (50). Two Japanese and one United Discussion States patient had double primary melanoma (Table 1 ; Refs. 49, In a case series, associations between specific cancers and a 52, and 63). Meningioma was frequent in both series: 15 cases in syndrome such as WRN can be revealed by demonstrating a difference from the usual distribution of cancer by cell type Japan, 1 of them malignant (74), and 7 outside Japan. One in and/or site. In our study, a marked difference from the usual each series was multiple (45, 65); all the tumors described were intracranial, in the usual locations. Although meningioma in the distribution was found. The excess of non-epithelial cancers was due largely to sarcoma in both series. The annual incidence general population is predominately in women, the sex ratio of soft-tissue sarcoma at ages 25-64 was 0.9/100,000 in the (male:female) in Japanese with WRN was 12:2 (1 sex un- general population of Osaka (143). If one assumes that in Japan known). the 8 10 known cases of WRN come from a total of 5000 cases Among the Japanese, eight cases had leukemia, specified [a high estimate based on genotype frequency estimates from as AML in five (84-88) and erythroleukemia in one (89). segregation analysis (5) and three times the prevalence in Precancerous hematological disorders consisted of five with MDS and/or myelofibrosis. Among Caucasians, two cases had inbred populations in Sardinia (144)], 1 soft-tissue sarcoma would be expected every 20 years, as compared with 23 cases leukemia (31, 94), one had MDS (95), and one had myelofibrosis (96). The sex was given in 13 of 14 Japanese with these observed in Japanese with WRN. One can view the Japanese data as establishing the excess, and the experience outside diagnoses, and all but one were male. Japan as confirmatory. Osteosarcoma (eight cases in Japan and The most frequent epithelial cancer among Japanese was thyroid carcinoma. Twenty Japanese cases were diagnosed pre- four elsewhere) was also excessive, given that its annual mci- dence in Osaka at ages 25-64 was 0.45/l00,000 (143). Osteo- mortem and 5 postmortem. The cell type was primarily follic- sarcoma, which normally has a peak in late adolescence, oc- ular or papillary. Only two Caucasians had thyroid cancer, one of them found at postmortem. Nonmelanotic skin cancers in Caucasians outnumbered those in Japanese 7 to 3. The Japanese had 38 other carcinomas M. Goto, personal case.

Table / Number of type-specific neoplasms and m yeloid disorders in WRN among Ja panese as compared with non-Japanese

Diagnosis Japan Refs. Outside Japan Refs.

Non-epithelial Soft-tissue sarcoma 23 7 Schwannoma, malignant 3 12-14 1 29 Rhabdomyosarcoma I 15 Malignant fibrous histiocytoma 6 16-20 Leiomyosarcoma 5 19, 21-24 Fibrosarcoma 5 5, 25, 26 3 30-32 Synovial sarcoma 1 27 Other or not specified 2 28 3 33-35

Osteosarcoma 8 + 1” 23, 36-42, P0” 4 29. 43,,45b Melanoma 21’ 3’ lntranasal 5 46-49 Esophageal I 50 Lip/face, acral I 5 1 1 63 Foot 13 23. 49, 52-61 Other 1 62 2 63.64 Meningioma 15 + 1 7 Multiple 1 65 1 45 Single (1 malignant; Ref. 74) 14 + 1 14, 25, 66-76, PC” 6 4, 77-81 Hematological disorders 14 4 Leukemia, probably RAEBd I 82 1 31 Atypical leukemia (MDS?) 1 83 Leukemia, acute myelogenous 5 84-88 1 94 Erythroleukemia I 89 MDS 2 67,90 1 95 MDS + myelofibrosis 2 91, 92 Myelofibrosis 1 68 1 96 Plasmacytoma 1 93 Brain tumors I 87 1 99 Total non-epithelial 82 + 2 26

Epithelial Thyroid carcinoma 20 + V’ I + l Follicular 9 + I 5, 6, 16, 2I, 22, 38, 89, 100, 101, 102, 103, PC” Papillary 8 14, 23, 37, 73, 85, 100, 104-106 i 109 Anaplastic 2 87, 103, l07 Other 1 78 Unknown I 67, 108 Gastriccarcinoma 6 23, 110-113 1 114 Hepatocellular carcinoma 3 5. 1 15, 1 16 1 1 17 Liver cancer. NOS 2 1 18, 1 19 Biliary carcinoma 4 120-123 1 77 Breast carcinoma 5 + I 5, 60, 113, 124, P0” 1 125 Skin carcinoma, non-melanotic 3 17, 19, 126 7 32, 114, 127-130 Other carcinoma 18 1 Nasal/nasopharyngeal 3 131-133 Laryngeal 2 5. 134 Pulmonary 1 135 Esophageal I 136 Pancreatic I 137 Urinary bladder 3 46, 138, 139 Uterine, NOS 2 38, 133 Ovarian 2 140, 141 Seminoma I 126 Renal cell I 14 Squamous cell, neck, NOS I 105 Prostatic I 142 Totalepithelial 61 + 2 11

Grand total 143 + 4 39

“ + I, personal observation (P0) of M. Goto (osteosarcoma, breast carcinoma); personal communications (PC) from A. Seki (meningioma) and K. Takakuwa (follicular thyroid carcinoma). b United States black patient (44). (. Two Japanese counted twice for double primary melanoma: intranasal, age 45, and toe, age 46 (49); right ankle, age 40, and left sole, age 44 (52); and a United States patient: ALM of thumb and lentigo maligna of the pinna (63). d RAEB, refractory anemia with excess of blasts; NOS, not otherwise specified. e Two Japanese had benign brain tumors (97, 98).

I Biopsy or surgery; excludes diagnoses at autopsy: five Japanese, one Caucasian. a Thyroid carcinoma diagnosed at autopsy.

Table 2 Multiple primary neoplasia or myeloid disorders in WRN

Case Diagnoses (sex, age) Ref.

Japan I Thyroid, follicular (F,” 27) + osteosarcoma (35) + uterus, NOS (34) 38 2 Thyroid, follicular (M. 39) + malignant fibrous histiocytoma (40) 16 3 Thyroid, follicular (F, 33) + erythroleukeniia (34) 89 4 Thyroid, papillary” + leiomyosarcoma + osteosarcoma + melanoma, plantar, 23 acral + gastric carcinoma (M, all at 45) 5 Thyroid, papillary (F, 40) + osteosarcoma (49) 37

6 Thyroid. papillary (F, 31) + MDS - AML (39) 38 7 Thyroid, papillary (M, 36) + squamous cell carcinoma, neck (38) 105 8 Thyroid. papillary (F, 43) + meningioma (44) 14 9 Thyroid, papillary (M, 46) + meningioma (46) 73 10 Meningioma (M, 44) + fibrosarcoma (44) 25 I 1 Meningioma (M, 59) + MDS (60) + thyroid,5 type unknown (62) 67 12 Meningioma (M, 34) + myelofibrosis after diphenythydantoin (41) 68 13 Schwannoma, malignant (M, 40) + renal cell carcinoma (43) 13 14 Intranasal melanoma (F, 45) + transitional bladder carcinoma (41) 46 15 Intranasal melanoma (F, 45) + ALM, toe (46) 49 16 Melanoma, acral, right ankle (M, 40) + left sole (44) 52 17 Gastric + breast, adenocarcinoma (F, 26) 1 13 18 Seminoma (M, 45) + skin, squamous cell carcinoma (55) 126 19 Uterine carcinoma NOS (F, age unknown) + nasopharyngeal carcinoma (age unknown) 133 Outside Japan

I ‘ Fibrosarcoma, mediastinum (M, 46) + multiple basal cell carcinoma, face (57) 32 2’ Melanoma: acral lentiginous, subungual + concurrent lentigo maligna, pinna (M, 56) 63 3’ Meningioma. multiple (M. age unknown) + osteosarcoma. orbital 45 4’ Meningioma (F, 42) + cholangiocarcinoma (42) 77 5’ Meningioma (F, 51) + ‘struma maligna” (48) 78

(, F, female; M, male; NOS. not otherwise specified. 5 Thyroid carcinoma at autopsy.

Table 3 W RN and neoplasia or myeloid disorders in first-degree relatives tomic sites have an origin in common, different from that of superficial spreading and nodular melanoma. The same sug- Family Diagnoses Relatives Refs. gestion had been made with regard to an apparent excess of Japan mucosal melanoma and ALM among blacks (147). I 2 MFH”. I leiomyosarcoma 3 siblings 19 Each series had a substantial number of meningioma. 2 2 fibrosarcoma, leg Brothers 5 These tumors, when benign, as in all but one of our cases, are 3 2 soft-tissue sarcoma Siblings 28 not recorded in tumor registries, so the incidence is not known. 4 2 intranasal melanoma Sisters 46 In large series, up to 25% of brain tumors have been reported 5 2 breast. I melanoma, nodular 3 sisters 60 to be meningioma (reviewed by Willis; Ref. 148). Among 6 2 gastric + 4 more primaries Son, father 23 7 1 leukemia. I hepatocarcinoma MZ” twins 82, 1 16 patients with WRN, other brain tumors have been reported in 8 I esophageal, I pancreatic Siblings 136, 137 only three Japanese (two were benign) and one Spaniard. Thus, 9 1 astrocytoma. I thyroid Brothers 87 the ratio of meningioma to other brain tumors is much higher Outside Japan than usual in WRN. I ‘ I malignant fibroxanthoma, 1 leukemia Siblings 31 Two Japanese with meningioma later developed a precur-

(‘ MFH, multiple fibrous histiocytoma; MZ, monozygous. sor of myelogenous leukemia: MDS in one, and myelofibrosis after treatment with diphenylhydantoin in the other. No report of meningioma with myelogenous leukemia or its precursors was found in the world literature. curred in all but 1 of 13 cases at 35-56 years. The exception MDS with WRN has been reported in three other Japanese was a 20-year-old.5 (two later developed myelofibrosis; Refs. 91 and 92) and one In Caucasians, the commonest types of melanoma are Turkish patient (95). Myelofibrosis following MDS, long re- superficial spreading and nodular. These types are rare in Jap- garded as an oddity, has recently been reported as a distinct anese and affected only one person with WRN. ALM typically clinicopathological entity in 17 cases (10 primary and 7 sec- affects the palms, soles, and mucosa and differs histologically ondary to radiochemotherapy; Ref. 149). Myelofibrosis without from superficial spreading and nodular melanoma (145). The MDS was reported in a Japanese (68) and a Sardinian (96). All rate for ALM is about 0.16 cases/lOO,000 people/year in Jap- of the leukemia cases with cell type specified were nonlym- anese, as it is in all races (146). Virtually no cases would be phocytic. The cases outside Japan strengthen the belief that the expected among 5000 people with WRN over a 20-year inter- occurrence of AML and its precursors in Japanese with WRN val. The I 3 melanoma on the feet and 5 in the nasal passages of Japanese with WRN suggests that melanoma at these ana- did not occur by chance. Follicular and papillary thyroid carcinoma, in excess among Japanese with WRN, have to our knowledge not been described together previously in any other genetic disorder,

5 M. Goto, personal case. except perhaps for familial adenomatous polyposis (150). Pap-

illary carcinoma is transmitted as an autosomal dominant trait learning the effects of its gene on normal and abnormal devel- in a few families ( 15 1 ). In a study of 536 autopsies in Japan, the opment. This is especially true of neoplasia, which is markedly prevalence of occult thyroid carcinoma was about I 8%; almost different from usual in WRN than in the normal geriatric all of these cases were papillary (I 52). Only one papillary population. Laboratory research into the origins of the diverse tumor was found at autopsy in our Japanese series. In any event, neoplasms in WRN should reveal important clues to tumori- the 20 clinical cases constitute a marked excess of thyroid genic mechanisms in the general population. cancer of diverse types in Japanese with WRN. The prepon- derance of the follicular type in WRN is unusual (153). Note Added in Proof A prominent feature of WRN is atrophy and wasting of the soft tissue and muscles of the limbs, giving the patient a spindly A candidate gene for the WRN locus has been identified (C. E. Yu et a!., A candidate gene for the WRN locus, Science. in press). appearance and scleroderma-like lesions of the hands, feet, and face (154). The high frequency of soft-tissue sarcoma and osteosarcoma in a connective tissue disorder raises the question References of a causal relationship. No excess of these sarcomas has been I. Epstein, C. J., Martin, G. M., Schultz, A. L., and Motulsky, A. G. Werner’s reported in other connective-tissue disorders, and the excess syndrome: a review of symptomatology, natural history, pathologic features, genetics and relation to the natural aging process. Medicine (Baltimore), 45: cancer in WRN is not limited to these sarcomas. 177-221, 1966. Chromosomal instability is seen in other genetic disorders 2. Goto, M., Rubenstein, M., Weber, J., Woods, K., and Drayna, D. Genetic with high risk of cancer (Bloom syndrome, Fanconi syndrome, linkage of Werner’s syndrome to five markers on chromosome 8. Nature (Lond.), and ataxia-telangiectasia). The pattern of aberrations in WRN is 355: 735-738, 1992. dissimilar: it is called “variegated translocation mosaicism” 3. Yu, C-E., Oshima, J., Goddard K. A. B . Mild. T., Nakura, J., Ogihara. T.. because the abnormalities range from the partial deletion of a Poot, M., Hoehn, H., Fraccaro, M., Puissan, C., Martin, G. M., Schellenberg, G. single chromosome to multiple translocations of several chro- D., and Wijsman, E. M. Linkage disequilibrium and haplotype studies of chromosome 8pl 1.1-21 .1 markers and Werner syndrome. Am. J. Hum. Genet.. 55: mosomes, some occurring as clones (reviewed by Salk; Ref. 4). 356-364, 1994. The array of neoplasms in WRN differs from those in the 4. Salk, D. Werner’s syndrome: a review of recent research with a review of classic instability syndromes, which are associated with leuke- connective tissue metabolism, growth control of cultured cells and chromosomal mia and/or lymphoma, and carcinoma of several sites (155- aberrations. Hum. Genet., 62: 1-15, 1982. 157). 5. Goto, M., Tanimoto, K., Horiuchi, Y., and Sasazuki, T. Family analysis of Survivors of atomic-bomb exposure have chromosome Werner’s syndrome: a survey of 42 Japanese families with a review of the literature. Clin. Genet., 19: 8-15, 1981. aberrations that last for decades. Medical X-ray exposures increase the risk of certain types of cancer that overlap those in 6. Sato, K., Goto, M., Nishioka, K., Arima, K., Hon, N.. Yamashita, N., Fujimoto, Y., Nanko, H., Ohara K., and Ohara, K. Werner’s syndrome associated excess in WRN: at low doses, AML and thyroid carcinoma; at with malignancies: five cases with a survey of case histories in Japan. Gerontol- high doses, soft-tissue sarcoma, osteosarcoma, and meningioma ogy, 34: 212-218, 1988. (reviewed by Miller; Ref. 158). Every prefecture in Japan 7. Knudson, A. G. Mutation and cancer: statistical study of retinoblastoma. Proc. contributed to the case series; there was no excess of WRN with NatI. Acad. Sci, USA, 68: 820-823, 1971. cancer near Hiroshima or Nagasaki. High risk of cancer after 8. Miller, R. W., Fraumeni, J. F., Jr., and Manning, M. D. Association of Wilms’ medical radiation exposure of WRN patients is a possibility that tumor with aniridia, hemihypertrophy and other congenital malformations. N. EngI. J. Med., 270: 922-927, 1964. we were unable to test because of lack of information. 9. Li, F. P., and Fraumeni, J. F., Jr. Soft-tissue sarcomas, breast cancer, and other In WRN, the excess of cancer is from 25-65 years of age. neoplasrns: a family cancer syndrome? Ann. Intern. Med., 7/: 747-752, 1969. Because the clinical signs of WRN are not apparent until the 10. Goto, M., Horiuchi, Y., Tanimoto, K., Ishii, T., and Nakashima, H. Werner’s third decade, the occurrence of an increase in childhood tumors syndrome: analysis of 15 cases with a review of the Japanese literature. J. Am. would have been unrecognizable. No suggestion of an excess Geriatr. Soc., 26: 341-347, 1978. was seen, however, in the available family histories of patients II . Miller, R. W., and Myers, M. H. Age distribution of epithelial and non- with WRN. epithelial cancers. Lancet, 2: 1250, 1983. In LFS, diverse multiple primary cancers may develop 12. Murano, S., Umeda, T., Saito, K., Yoshida, S., and Kuwahara, T. A case of (including soft-tissue sarcoma and osteosarcoma). Familial can- Werner’s syndrome associated with malignant schwannoma. Jpn. J. Gerontol., 29: 240, 1992. cer aggregation is more common (1 59) than in WRN, in accord 13. Matsurnoto, I., Murano, S., Saito, K., Yoshida, S., Umeda, T., and Kuwahara, with the clinical mode of transmission (autosomal dominant in T. Carcinogenesis in Werner’s syndrome. Jpn. J. Gerontol., 30: 169, 1993. LFS and recessive in WRN). The unusual array of cancers in 14. Sugimoto, N., Terayama, K., Fujioka, F., and Maeda, T. Four cases of LFS is often due to a germline mutation of the p53 gene that Werner’s syndrome with special reference to the orthopedic aspect. Chubu affects cell cycle control (160). The gene for WRN appears also Nippon Orthop. Surg. Traumatol., 34: 786-790, 1991. to play an important role in oncogenesis and programmed cell 15. Nanko, H., Atsumi, R., Takahashi, K., and Murata, K. The histopathological death. and ultrastructural observations of poorly differentiated rhabdomyosarcoma in Werner’s syndrome. Arch. Koseinennkinn Hosp., 13: 395-404, 1986. Other unusual features of WRN include diminished sur- vival of its fibroblasts in culture (about 20 instead of 60 dou- 16. Yamaga, Y., Nishiyama, Y., Kato, Y., Toya, Y., Niimi, M., Fukaya, M., and Azumi, T. A case of Werner’s syndrome without short stature. Jpn. J. Intern. blings normally, according to Faragher et a!.; Ref. 161), a Med., 84: 1361, 1995. diminished level of telomerase, associated in the general pop- 17. Ohno, M., Tomita, K., Tsuchiya, H., Matsubara. F., Inaoki, M., and ulation with aging (162, 163), and a disequilibrium of genetic Kawashima, K. Werner’s syndrome with malignant tumors; report of three cases. markers near the WRN gene locus in Japanese but not in Oi-thop. Surg. Traumatol., 33: 1293-1298, 1990. Caucasians, with haplotype differences within and between the 18. Ono, 1., Hara, A., Ogata, A., and Furuki, H. Malignant fibrous histiocytoma. two races, suggesting multiple independent mutations (3), Hifu Rinsho, 24: 451-457, 1982. which may relate to the difference in tumor types observed. 19. Usui, M., Ishii, S., Yamawaki, S., and Hirayama. T. The occurrence of soft tissue sarcomas in three siblings with Werner’s syndrome. 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M Goto, R W Miller, Y Ishikawa, et al.

Cancer Epidemiol Biomarkers Prev 1996;5:239-246.

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