National Cancer Institute – Cancer Research Portfolio
Salivary Gland Cancer Research Projects

Projects as of date: 9/24/02:

Current Project Descriptions:

Localized Therapies –
Clinical Applications Research Projects:

#1 - Second cancers following Hodgkin's disease

Principal Investigator: Ron, Elaine
NCI Program Director: Travis
Project ID: Z01, CP10131-Sub-70-97-06
Years Funded Since 1997: 2001

The Branch has a long-standing involvement in the systematic evaluation of chemotherapeutic drugs alone or in combination with radiotherapy. As more individuals become long-term cancer survivors, there is greater need to evaluate risk-benefit ratios for various treatment protocols. Branch studies have shown that platinum-based chemotherapy for ovarian cancer was linked to a four-fold risk of leukemia; however, the substantial benefit that platinum-based treatment offers, outweighs the relatively small excess risk of leukemia. A study of leukemia following radiotherapy for testicular cancer revealed a three-fold elevated risk for leukemia, and this risk increased with increasing radiation dose to active bone marrow.

The Branch is currently conducting an international cohort study of 32,000 Hodgkin's disease patients to evaluate the risk of radiation and chemotherapy induced second cancers. A study focusing on a subset of 6,000 children and adolescents with Hodgkin's disease indicated a high risk for second cancers of the thyroid and respiratory tract in patients treated before age ten; at older ages, the highest risks were seen for cancers of the digestive tract and breast.

An evaluation of new cancers in 28,884 allogeneic BMT recipients demonstrated an increased risk of solid tumors developing among long term survivors. Compared to an age- and sex- matched general population, transplant recipients were at significantly higher 2.3-fold risk of developing new invasive solid cancers. Risk increased with time since transplantation with a nearly 5-fold risk seen among 10 year survivors. The cumulative incidence of invasive second cancers for all patients was 8.1% ± 3.1% at 20 years after transplantation. Sites with significantly increased risk of second cancers were oral cavity, salivary, liver, melanoma, brain, thyroid and bone/connective tissue. While breast cancer risk was not higher than in the general population in early post-transplant time periods, 10-year survivors had a significantly increased risk.

A cohort of 1,600 Retinoblastoma(RB) patients continues to be followed to monitor their cancer risk, and RB patients who have developed melanoma are undergoing clinical examination for dysplastic nevi syndrome, lipomas, and mutations in melanoma susceptibility genes. Recent Branch research has demonstrated that children treated for germ-line RB experience a markedly increased risk of lung cancer likely due to somatic mutations of the RB-1 gene are involved in the development of lung cancer. A newsletter informing RB patients of their second cancer risk and preventive measures for smoking cessation was circulated.

In collaboration with the Genetic Epidemiology Branch and cancer registries in four Nordic countries, breast cancer risk was reported to be increased in mothers, but not other female relatives, of patients with ataxia-telangiectasia. Expansion of the original cohort and sequencing of the ATM gene in patients and family members is also in progress.

A multi-center retrospective cohort study of 5,573 women with scoliosis revealed a statistically significant 1.7-fold risk of death from breast cancer. Patterns were consistent with a radiation etiology in that risk increased with increasing number of diagnostic x-ray examinations and estimated cumulative radiation dose to the breast. Potential confounding between radiation dose and severity of scoliosis may explain some of the excess risk observed.

The Branch is currently estimating the risk of cancer after exposure to Thorotrast among several large populations. Thorotrast, once used as an angiographic contrast agent, is not excreted from the body to any appreciable extent; and has induced high rates of liver angiosarcoma and leukemia. The Branch recently completed a 40-year mortality follow-up of 693 Swedish patients with neurological disorders who received Thorotrast. A significant dose-response relation was found for all causes of death combined, and all malignant tumors combined.

A second followup study of cancer mortality in a cohort of 2000 irradiated and 2000 surgically treated peptic ulcer patients is in progress. Analyses are focused on increased risks of stomach, pancreatic and lung cancer following radiotherapy in long-term survivors.

A retrospective cohort study of cancer mortality in 5,300 subjects treated with nasopharyngeal irradiation (radium) during childhood and 5,200 control subjects in the Netherlands revealed excess deaths due to non-Hodgkin's lymphoma. No excess deaths due to cancers of head and neck were reported.

A feasibility of 500 neutron-treated cancer patients did not detect an increased risk of leukemia. Evaluation of chromosome aberrations following neutron exposure demonstrated that neutron-induced dicentrics and rings disappeared within the first three years after exposure, while translocations peristed for more than 17 years. Considerable variability in the number of aberrations between patients who received similar bone marrow doses was noted.

A cohort of female tuberculosis patients continues to be studied for the risk of breast cancer following multiple chest fluorscopies received during adolescence and early adult life. Previous studies indicated a dose-response relationship between number of fluorscopies and breast cancer.
Preparation of a monograph describing multiple primary cancers in SEER (1973-1998)is underway. The purpose is to clarify the patterns of multiple primary cancers in SEER through a comprehensive evaluation of cancer risk following each initial primary cancer, and to integrate these findings with published literature to further our understanding of cancer etiology.
Nested case-control studies of brain, breast and thyroid cancers following an initial childhood cancer are being planned within the large cohort of 5-year childhood cancer survivors. Studies will focus on treatment-induced second cancers. Detailed radiation dosimetry is in progress as well as methodologic work regarding control selection and issues of overmatching.

A dosimetry monograph describing methods that have been developed to estimate and reconstruct medical, environmental and occupational radiation exposures in epidemiologic studies conducted by the Branch is in progess.

Several studies of thyroid cancer etiology have been conducted. Pooled analyses of 12 international case-control studies of thyroid cancer concluded that goiter and benign nodules/adenomas are the strongest risk factors for thyroid cancer, apart from radiation in childhood. Menstrual and reproductive factors were weakly associated with thyroid cancer, but appeared stronger among women diagnosed at younger ages. A cohort of children irradiated in childhood for enlarged tonsils continues to be followed for the occurrence of thyroid and other head and neck cancers. A study investigating thyroid cancer risk following diagnostic x-rays is comparing medical record data with questionnaire data to evaluate recall bias. Methodologic studies are evaluating dose uncertainty in a study of radiation-induced thyroid cancer in a cohort of Israeli children treated for tinea capitis.

The Branch is also evaluating the risk of cancer following diagnostic and therapeutic Iodine-131 in several large, international study populations.

Cancer mortality following radiation treatment for benign gynecologic disease in a cohort of 12,000 women is being updated to evaluate solid tumor risk.

This project is coded as follows:

Type of Cancer Research Codes:
* Exogenous Factors in the Origin and Cause of Cancer
* Localized Therapies - Clinical Applications

Type of Cancer Codes:
* Bladder Cancer
* Blood Cancer
* Breast Cancer
* Endometrial Cancer
* Esophageal Cancer
* Gastrointestinal Tract
* Genital System, Female
* Head and Neck Cancer
* Leukemia
* Lung Cancer
* Melanoma
* Respiratory System
* Salivary Gland Cancer
* Sarcoma, Soft Tissue
* Urinary System

Parent Project:
Studies of Medical Radiation and Other Therapeutic Agents CP10131

Cancer-Related Biology Research Projects:

#2 - Tissue Specific Tumor Induction by Polyomavirus

Principal Investigator: Cerny, Jan
Institution: University of Maryland Balt Prof School
State: MD

NCI Program Director: Wong, May
NCI Division: Division of Cancer Biology
Project ID: R29, CA63111
Project Funding Period: 2/01/95 to 1/31/01

Polyomavirus normally establishes a silent, persistent infection in its natural host, the mouse, but under experimental conditions can cause widespread lytic infection and induce tumors in up to a dozen different tissues, including a high frequency of tumors in thymic tissue, salivary glands and mammary glands. Although the virus has been studied extensively in cell culture, little is known about its interaction with host cells in the animal. The experiments in this proposal are designed to explore the virus-cell interactions that result in tissue specificity of tumor formation by polyomavirus. The two specific aims in this proposal are based on the hypothesis that viral regulatory sequences interacting with cellular factors are responsible for tissue specific tumor induction. The first goal is to define the viral genetic determinants responsible for tissue specific tumorigenesis by evaluating the tumor profile of viruses containing mutations in potential regulatory sequences. These regulatory regions include a 4Obp duplication of sequences on the early side of the origin of replication that we have previously shown to be necessary for the induction of thymic epitheliomas, and the polyoma enhancer sequences that are important for virus regulation in cell culture systems. Our second goal is to use these regulatory sequences to identify and characterize the cellular factors that bind to them. The DNA binding proteins will be identified by gel shift and footprinting experiments and further characterized by UV crosslinking experiments and affinity chromatography. Polyomavirus gene expression and replication, as well as the oncogenic pathways triggered by the virus, utilize cellular factors that are normally involved in signal transduction and cell growth control, and that are altered in many cancers of non-viral etiology. Thus, understanding tumor induction by polyomavirus at the molecular level and identifying cis-acting sequences and cellular factors involved in the tissue specificity of tumor formation will provide new information relevant to the fields of cell growth control and cancer.

This project is coded as follows:

Type of Cancer Research Codes:
* Cancer-Related Biology
* Exogenous Factors in the Origin and Cause of Cancer

Type of Cancer Codes:
* Breast Cancer
* Genital System, Male
* Head and Neck Cancer
* Not Site-Specific Cancer
* Prostate Cancer
* Salivary Gland Cancer
* Thymoma, Malignant

Endogenous Factors in the Origin and Cause of Cancer Research Projects

#3 - Mechanisms Regulating Reversal of Premalignancy

Principal Investigator: Furth, Priscilla
Institution: Georgetown University
State: DC

NCI Program Director: Spalholz, Barbara
NCI Division: DCB
Project ID: R01, CA89041
Project Funding Period: 12/15/00 to 11/30/05

No abstract available for this Project.ID.

This project is coded as follows:

Type of Cancer Research Codes:
* Application of Model Systems
* Endogenous Factors in the Origin and Cause of Cancer

Type of Cancer Codes:
* Head and Neck Cancer
* Salivary Gland Cancer

Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors Research Projects

#4 - Studies of Atomic Bomb Survivors

Principal Investigator: Land, Charles

Project ID: Z01, CP10134
Project Funding Period: 10/01/00 to 9/30/01

A cohort of 94,000 survivors of the Hiroshima and Nagasaki atomic bombings is being studied in collaboration with the Radiation Effects Research Foundation (RERF). Cohort studies are used to quantify radiation dose response and its dependence on histological subtype of tumor, age at exposure, sex, age at observation, and time following exposure. Among several new findings is the excess risk of basal cell, but not squamous cell carcinoma of the skin associated with radiation exposure. The radiation related risk was markedly increased as age at exposure decreased. No evidence was found for an interaction with ultraviolet radiation.There is suggestive evidence for excess risks of melanoma and Bowen's disease of the skin. A radiation related excess risk was also found for tumors of the nervous system and the risk was especially high for Schwannoma. Also, liver cancer risk was found to be strongly related to radiation dose, and there was some evidence of synergy between radiation and hepatitis C viral infection as liver cancer risk factors. A study of Salivary gland tumors found a marked excess of radiation-related tumors, largely limited to mucoepidermoid carcinoma and Warthin's tumor.

Case ascertainment has been completed in studies of tumors of the breast, thyroid, and ovary, and manuscripts are in preparation. Relative to age-specific baseline rates, the radiation-related excess risk of breast cancer following exposure at young ages (<20) was considerably higher for diagnosis before age 35 than later; however, it has remained flat thereafter, showing no sign of decline over the interval 35-65 years of age. Furthermore, in modeling the excess relative risk per unit dose as a function of age at exposure, women who were exposed before age 20 have the highest risk; and women who were exposed at 40 years of age or older have the least risk. There is no indication that exposure around the ages of menarche or breast budding carries more risk than exposure during early childhood or late adolescence. Case ascertainment is also in progress for lung and lymphoid cancers.

A significantly increased breast cancer risk was associated with level of unbound estradiol determined from stored serum obtained from women who later developed breast cancer and from similar controls. These data were included in a combined analysis of comparable data from several other studies, which confirmed the main result and also found a protective effect of sex hormone binding globulin. A research protocol has been submitted for a new, expanded A-bomb survivor study with twice as many breast cancer cases, utilizing more recent stored serum samples and measurement of additional hormones. A new, very large record-based study of breast cancer has been initiated to verify and refine earlier findings of interactions between reproductive history and radiation dose.

A case-case approach is being used to study genetic susceptibility to radiation-related breast and ovarian cancer. The previously reported phenomenon of extremely high, dose-specific relative risks for early-onset breast cancer (before age 35) is suggestive of increased sensitivity to radiation among a genetically predisposed population subgroup, and an interesting subject for further investigation. A research protocol has been approved and archival tissues are being collected for a collaborative study, with the RERF Dept. of Radiobiology, of molecular alterations in early-onset breast and ovarian cancers among A-bomb survivors.

This project is coded as follows:

Type of Cancer Research Codes:
* Exogenous Factors in the Origin and Cause of Cancer
* Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors

Type of Cancer Codes:
* Bladder Cancer
* Blood Cancer
* Brain Tumor
* Breast Cancer
* Colon and Rectal Cancer
* Gastrointestinal Tract
* Genital System, Female
* Head and Neck Cancer
* Hodgkin's Disease
* Lung Cancer
* Melanoma
* Nervous System
* Ovarian Cancer
* Respiratory System
* Salivary Gland Cancer
* Skin Cancer
* Urinary System

Sub-projects associated with this project:
Cancer risk among Japanese A-bomb survivors CP10134-Sub-70-79-00

Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors Research Projects

#5 - Cancer risk among Japanese A-bomb survivors

Principal Investigator: Land, Charles

NCI Program Director: Land
Project ID: Z01, CP10134-Sub-70-79-00
Years Funded Since 1997: 2001

A cohort of 94,000 survivors of the Hiroshima and Nagasaki atomic bombings is being studied in collaboration with the Radiation Effects Research Foundation (RERF). Cohort studies are used to quantify radiation dose response and its dependence on histological subtype of tumor, age at exposure, sex, age at observation, and time following exposure. Among several new findings is the excess risk of basal cell, but not squamous cell carcinoma of the skin associated with radiation exposure. The radiation related risk was markedly increased as age at exposure decreased. No evidence was found for an interaction with ultraviolet radiation.There is suggestive evidence for excess risks of melanoma and Bowen's disease of the skin. A radiation related excess risk was also found for tumors of the nervous system and the risk was especially high for Schwannoma. Also, liver cancer risk was found to be strongly related to radiation dose, and there was some evidence of synergy between radiation and hepatitis C viral infection as liver cancer risk factors. A study of Salivary gland tumors found a marked excess of radiation-related tumors, largely limited to mucoepidermoid carcinoma and Warthin's tumor.

Case ascertainment has been completed in studies of tumors of the breast, thyroid, and ovary, and manuscripts are in preparation. Relative to age-specific baseline rates, the radiation-related excess risk of breast cancer following exposure at young ages (<20) was considerably higher for diagnosis before age 35 than later; however, it has remained flat thereafter, showing no sign of decline over the interval 35-65 years of age. Furthermore, in modeling the excess relative risk per unit dose as a function of age at exposure, women who were exposed before age 20 have the highest risk; and women who were exposed at 40 years of age or older have the least risk. There is no indication that exposure around the ages of menarche or breast budding carries more risk than exposure during early childhood or late adolescence. Case ascertainment is also in progress for lung and lymphoid cancers.

A significantly increased breast cancer risk was associated with level of unbound estradiol determined from stored serum obtained from women who later developed breast cancer and from similar controls. These data were included in a combined analysis of comparable data from several other studies, which confirmed the main result and also found a protective effect of sex hormone binding globulin. A research protocol has been submitted for a new, expanded A-bomb survivor study with twice as many breast cancer cases, utilizing more recent stored serum samples and measurement of additional hormones. A new, very large record-based study of breast cancer has been initiated to verify and refine earlier findings of interactions between reproductive history and radiation dose.

A case-case approach is being used to study genetic susceptibility to radiation-related breast and ovarian cancer. The previously reported phenomenon of extremely high, dose-specific relative risks for early-onset breast cancer (before age 35) is suggestive of increased sensitivity to radiation among a genetically predisposed population subgroup, and an interesting subject for further investigation. A research protocol has been approved and archival tissues are being collected for a collaborative study, with the RERF Dept. of Radiobiology, of molecular alterations in early-onset breast and ovarian cancers among A-bomb survivors.

This project is coded as follows:

Type of Cancer Research Codes:
* Exogenous Factors in the Origin and Cause of Cancer
* Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors

Type of Cancer Codes:
* Bladder Cancer
* Blood Cancer
* Brain Tumor
* Breast Cancer
* Colon and Rectal Cancer
* Gastrointestinal Tract
* Genital System, Female
* Head and Neck Cancer
* Hodgkin's Disease
* Lung Cancer
* Melanoma
* Nervous System
* Ovarian Cancer
* Respiratory System
* Salivary Gland Cancer
* Skin Cancer
* Urinary System

Parent Project:
Studies of Atomic Bomb Survivors CP10134

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