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Context: There is a substantial risk of a second cancer for persons with hereditary retinoblastoma, which is enhanced by radiotherapy., Objective: To examine long-term risk of new primary cancers in survivors of childhood retinoblastoma and quantify the role of radiotherapy in sarcoma development., Design: Cohort incidence study of patients with retinoblastoma followed for a median of 20 years, and nested case-control study of a radiation dose-response relationship for bone and soft tissue sarcomas., Setting/participants: A total of 1604 patients with retinoblastoma who survived at least 1 year after diagnosis, identified from hospital records in Massachusetts and New York during 1914 to 1984., Results: Incidence of subsequent cancers was statistically significantly elevated only in the 961 patients with hereditary retinoblastoma, in whom 190 cancers were diagnosed, vs 6.3 expected in the general population (relative risk [RR], 30 [95% confidence interval, 26-47]). Cumulative incidence (+/-SE) of a second cancer at 50 years after diagnosis was 51.0% (+/-6.2%) for hereditary retinoblastoma, and 5.0% (+/-3.0%) for nonhereditary retinoblastoma. All 114 sarcomas of diverse histologic types occurred in patients with hereditary retinoblastoma. For soft tissue sarcomas, the RRs showed a stepwise increase at all dose categories, and were statistically significant at 10 to 29.9 Gy and 30 to 59.9 Gy. A radiation risk for all sarcomas combined was evident at doses above 5 Gy, rising to 10.7-fold at doses of 60 Gy or greater (P<.05)., Conclusions: Genetic predisposition has a substantial impact on risk of subsequent cancers in retinoblastoma patients, which is further increased by radiation treatment. A radiation dose-response relationship is demonstrated for all sarcomas and, for the first time in humans, for soft tissue sarcomas. Retinoblastoma patients should be examined for new cancers and followed into later life to determine whether their extraordinary cancer risk extends to common cancers of adulthood.

We investigated the report of a community cluster of cancers in 33 children, which included two siblings known to have dominantly inherited Li-Fraumeni syndrome and a germline p53 mutation. After defining criteria for inclusion in the cluster, the 12 eligible childhood cancer probands diagnosed between 1980 and 1989 were not excessive (expected, ten cases). The corresponding childhood cancer mortality rates for the community fluctuated between 1950 and 1989 and were not increased overall. However, three additional probands had family histories of childhood cancer that suggested a forme fruste of Li-Fraumeni syndrome. The epidemiological data suggested a geographic cluster of this rare hereditary disorder, but absence of germline p53 mutation in the three other multicase families indicates genetic heterogeneity. Laboratory studies can assist analyses of suspected clusters, although investigations of geographic clusters of hereditary cancers raise complex issues of confidentiality and protection of affected individuals, their families, and the community.

Malignant peripheral nerve sheath tumors (MPNST) are known to develop in patients with neurofibromatosis 1 (NF1), thus providing an excellent model for the study of multistep carcinogenesis in genetically predisposed individuals. To determine the sites of gene(s) involved in such a process, we have performed cytogenetic analysis on 10 tumors. The patients were five males and five females ranging in age from 15 to 77 years. Nine patients had NF1. Karyotypic analysis of these tumors exhibited complex clonal abnormalities of several chromosomes. Recurrent abnormalities (numerical as well as structural) of chromosomes 1, 11, 12, 14, 17, and 22 occurred in a substantial proportion of tumors studied. Although abnormalities of these chromosomes have been seen in a variety of other tumors, the aberrations of chromosomes 17 and 22 are of particular interest; chromosomes 17 and 22 carry the genes for NF1 and NF2, respectively. In addition to other clonal aberrations, six tumors had abnormalities of both chromosomes 17 and 22, while three tumors only had an abnormality of chromosome 17. In eight tumors a structural abnormality of chromosome 17 included deletion or a relative deficiency of 17p; in four of the tumors there was also either deletion or rearrangement of the NF1 locus at the cytogenetic level. One tumor had monosomy of chromosome 17. The abnormality of chromosome 22 was deletion of 22q11.2-->qter. This study suggests that the germline mutation in one of the copies accompanied by loss or inactivation of the second copy of the NF1 gene and tumor suppressor gene(s) on 17p and 22q may be associated with the neoplastic transformation; abnormalities of other chromosomes may be related to progression of MPNST. Although the role of the p53 gene in carcinogenesis is well documented in several tumor types, the role of the NF2 gene or other unidentified tumor suppressor gene(s) on chromosomes 22q, 1p, 11, 12, 14 remains to be seen.

Cytogenetic analysis of a low-grade metastatic endometrial stromal sarcoma in a 58-year-old woman revealed translocations involving both homologues of chromosome 7 with chromosomes 13 and 17, respectively, and an interstitial deletion of the long arm of chromosome 11. The karyotype of the tumor was 46,XX,t(7;13)(q11.1;p13),t(7;17)(p21;q12),del(11)(q13q21).

Chromosomal analysis of two pulmonary metastases from a 25-year-old male with alveolar soft-part sarcoma of the right lower extremity revealed multiple and complex chromosomal abnormalities. The rearrangements included deletions and translocations affecting chromosomes 1, 2, 3, 10, 11, 14, 15, and 16. Trisomy of chromosome 12 and loss of chromosome 17 was also observed.

Relatives of 88 long-term survivors of childhood sarcoma were examined for the familial cancer syndrome of sarcoma, breast cancer, and other neoplasms (Li-Fraumeni syndrome). Twenty-six of 402 close relatives developed cancer (expected, 23.8), including breast cancer in four mothers (expected, 3.1). Two sarcoma probands who developed second malignant tumors have multiple relatives with cancer and might have an inherited predisposition. An increased cancer risk and exceptional requirement for disease screening appear to be confined to first-degree relatives of a small fraction of children with sarcoma, notably probands with second cancers.

Choroid plexus neoplasms are rare epithelial tumors of the central nervous system. A carcinoma of the choroid plexus occurred in a child from a family with the breast cancer-sarcoma syndrome (Li-Fraumeni or SBLA syndrome), an inherited condition characterized by the development of diverse neoplasms (sarcoma, breast cancer, brain tumors, leukemia, adrenal cortical carcinoma, and others). Choroid plexus carcinomas were identified in two kindreds previously reported with the syndrome. The literature contains reports of choroid plexus neoplasms occurring in families and in individuals with multiple primary tumors. Choroid plexus neoplasm may be a manifestation of the inherited proclivity to tumor development in the breast cancer-sarcoma syndrome.

Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.

A poorly differentiated sarcoma in a 32-year-old female revealed a large, abnormally banded region in one chromosome #8 in all metaphases. The modal karyotype was 46,XX, -8, +mar. Southern blot hybridization was performed with probes for two protooncogenes located in chromosome 8q (c-MYC and c-MOS). No amplification or rearrangement was observed to account for the cytogenetic abnormality.

Osteosarcoma or chondrosarcoma developed as a second malignant neoplasm (SMN) in 40 of 188 individuals with SMN whose first neoplasm occurred in childhood. A genetic susceptibility to cancer was found in 23; the SMN developed in an irradiated field in 32; both factors wer present in 16; neither in one. When a genetic predisposition was present, radiation shortened the interval to SMN. The intervals between tumors and the age at which the bone sarcomas developed in relation to genetic disease and therapy were analyzed by a two-mutation hypothesis. Studies of SMN in childhood permit us to make observation about the role of genetic factors and environmental mutagens in cancer etiology.

A 37-year-old woman with a history of bilateral mesenchymal cystic hamartomata of the lung was subsequently found to have low-grade endometrial stromal sarcoma. Cytogenetic analysis of the uterine tumor revealed, in all metaphases, an unusual derivative chromosome generated by the insertion of chromosome 19 into chromosome 10 at the level of its centromere [ins(10;19)(p11;p13q13)].

Retinoblastoma is a childhood tumor that can arise because of mutant alleles acquired as somatic or germinal mutations. The mutant allele can be carried in the germ line. The mutations creating these alleles act by inactivating copies of a recessive oncogene located within band q14 of chromosome 13 and termed the RB1 locus. We have reported isolation of a cDNA fragment that recognizes chromosomal sequences possessing many of the attributes of the retinoblastoma gene associated with the RB1 locus. We now report that this segment is additionally the target of somatic mutations in mesenchymal tumors among patients having no apparent predisposition to retinoblastoma and no previous evidence of retinoblastoma. These tumors provide additional evidence that the cloned sequences are representative of a gene that is a frequent target of inactivation during tumorigenesis. Sequence analysis of this cDNA provides little insight into its normal functional role.

Observation of one kindred with sarcoma, breast cancer and other neoplasms has led to the recognition of a familial cancer syndrome in young patients. To date, 24 affected families have been enrolled in the Cancer Family Registry of the National Cancer Institute, and 21 others have been reported in the literature. The major feature of the syndrome is an autosomal dominant pattern of breast cancers and sarcomas of bone and soft tissue at unusually early ages. Additional components of the syndrome appear to be brain tumors, leukemia, and adrenocortical carcinoma in children and adolescents. Family members are prone to develop multiple primary cancer. In addition to descriptive reports, the syndrome has been detected in segregation analysis of a consecutive series of children with soft tissue sarcomas; in studies of breast cancer among mothers of unselected children with sarcomas; and in prospective observation for new cancers in our previously reported families. Laboratory studies are in progress to seek the gene(s) associated with this syndrome of diverse cancers. Studies of this rare disorder may provide new insights into the pathogenesis of the 5 component tumors, particularly breast cancer, the commonest cancer among women in the United States and elsewhere.

A translocation that involves chromosome X (band p11.2) and chromosome 18 (band q11.2) was observed in short-term in vitro cultures of cells from five synovial sarcomas and one malignant fibrous histiocytoma. In four of these tumors, the translocation t(X;18)(p11.2;q11.2) was reciprocal. The two other tumors had complex translocations: t(X;18;21)(p11.2;q11.2;p13) and t(X;15;18)(p11.2;q23;q11.2). A translocation between chromosomes X and 18 was not detected in other histological types of soft tissue sarcoma. The X;18 rearrangement appears to characterize the synovial sarcoma and is the first description of a primary, nonrandom change in the sex chromosome of a human solid tumor.

We estimated the risk of subsequent bone cancer among 9170 patients who had survived two or more years after the diagnosis of a cancer in childhood. As compared with the general population, the patients had a relative risk of 133 (95 percent confidence interval, 98 to 176) and a mean (+/- SE) 20-year cumulative risk of 2.8 +/- 0.7 percent. Detailed data on treatment were obtained on 64 patients in whom bone cancer developed after childhood cancer. As compared with 209 matched controls who had survived cancer in childhood but who did not have bone cancer later, patients who had had radiation therapy had a 2.7-fold risk (95 percent confidence interval, 1.0 to 7.7) and a sharp dose-response gradient reaching a 40-fold risk after doses to the bone of more than 6000 rad. The relative dose-response effect among patients who had been treated for retinoblastoma resembled that among patients with all other types of initial tumors, although the cumulative risk of bone cancer in the retinoblastoma group was higher. Similar numbers of patients were treated with orthovoltage and megavoltage; the patterns of risk among categories of doses did not differ according to the type of voltage. After adjustment for radiation therapy, treatment with alkylating agents was also linked to bone cancer (relative risk, 4.7; 95 percent confidence interval, 1.0 to 22.3), with the risk increasing as cumulative drug exposure rose. We conclude that both radiotherapy and chemotherapy with alkylating agents for childhood cancer increase the subsequent risk of bone cancer.