Risk Of Multiple Primary Malignancies Research Articles

Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study.

Li-Fraumeni syndrome, caused primarily by pathogenic or likely pathogenic germline TP53 variants, is a rare, variably penetrant, cancer predisposition syndrome with very high risks of cancer starting in childhood, including the risk of multiple primary malignancies over an individual's lifespan. We aimed to characterise and quantify cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants. This observational cohort study was done in 480 carriers of pathogenic or likely pathogenic germline TP53 variants enrolled in the National Cancer Institute's referral-based longitudinal Li-Fraumeni syndrome study between Aug 1, 2011, and March 24, 2020. Data on personal and family history of cancer were obtained through study questionnaires and validated by medical records. Variants were categorised on the basis of both loss-of-function (LOF) and dominant-negative effect (DNE) properties. Cancer incidence associated with Li-Fraumeni syndrome was compared with that of the general population using the Surveillance, Epidemiology, and End Results (SEER) 1975-2017 registry. Cancer incidence was evaluated with family-clustered Cox regression models and competing risk methods. This study is registered with ClinicalTrials.gov, NCT01443468. Individuals with Li-Fraumeni syndrome had a nearly 24 times higher incidence of any cancer than the general population (standardised incidence ratio 23·9; 95% CI 21·9-26·0), with the highest comparative incidence from childhood to 30 years of age. The overall cancer incidence remained 10·3 (95% CI 7·9-13·2) times higher than that of the general population after age 50 years. In women, when considering breast cancer as a competing risk, the probability of a first diagnosis of a non-breast cancer malignancy was substantially lower than that of any first cancer (24·4% [95% CI 19·6-30·5] vs 50·4% [43·5-56·5] by age 33·7 years). Overall, DNE_LOF and notDNE_LOF variants were associated with earlier age at first and second cancer compared with notDNE_notLOF and DNE_notLOF variants. The time interval from first to second cancer was shorter among carriers whose first cancer diagnoses were later in life. Multiple cancers were diagnosed within a short timeframe in some individuals, regardless of the order of cancer occurrence. This study adds granularity to the understanding of cancer incidence and patterns in individuals with pathogenic or likely pathogenic germline TP53 variants. Integration of age range-specific cancer incidence estimates, cancer-free survival by functional variant group, the potential impact of risk-reducing mastectomy on female cancer incidence, and data on subsequent malignancies will be important for the development of strategies to optimise cancer screening and management for these individuals. Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Institutes of Health.

Waiting and "weighted down": the challenge of anticipatory loss for individuals and families with Li-Fraumeni Syndrome.

Li-Fraumeni Syndrome (LFS) is characterized by risk of multiple primary malignancies in diverse sites, pediatric onset, near complete penetrance by age 70years, limited options for prevention, and substantial uncertainty regarding disease manifestation and prognosis. Forty-five families, including 117 individuals aged 13-81years, enrolled in the US National Cancer Institute's Li-Fraumeni Syndrome Study completed 66 interviews regarding their LFS experiences. An interdisciplinary team used modified grounded theory to examine family distress regarding expectations of loss and change due to likely cancer diagnoses, and the consequences of this likelihood across physical, social, and emotional domains. Disease-free periods were characterized by fearful anticipation of diagnosis or recurrence, uncertainty regarding post-treatment quality of life, and planning for shifts in family dynamics to enable caregiving. The chronicity of waiting for these changes incited dread and inhibited effective coping with the pragmatic, emotional, and existential challenges of the syndrome. Consequently, families reported high burden on roles and resources and limited guidance to prepare for, or achieve resolution with, grief. Anticipatory loss, the experience of bereavement prior to an expected change, distinguishes hereditary cancer risk from a sporadic diagnosis. Such grief is often incomplete in impact or meaning, subjected to rapid or profound change as conditions worsen, and poorly understood. In this study, losses were compounded by profound uncertainty, a chronic feature of LFS, which compromised mourning. Long-term engagement of mental health providers with bereavement training, in partnership with genetics providers, can provide invaluable educational and psychological support to families as they navigate these implacable challenges.

Multiple primary malignancies for squamous cell carcinoma and adenocarcinoma of the esophagus.

Patients with esophageal cancer (EC) frequently have multiple primary cancers. We conducted the present study to assess the risk of multiple primary malignancies for patients with squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the esophagus and to investigate the influence of multiple primary tumors on the prognosis of EC patients. Using the data of 44,091 EC patients from the Surveillance Epidemiology and End Results (SEER) database, we calculated the standardized incidence ratios (SIRs) for overall multiple primary cancers and cancers at particular sites among EC survivors. The SIRs of esophageal SCC and AC patients were compared using Poisson regression. The Kaplan-Meier (KM) method was used for survival analysis. Multiple primary cancer risk was significantly increased among both esophageal SCC and AC survivors (SIR: 2.28 and 1.57, respectively; P<0.001). Among SCC patients, the highest SIRs were found in the oral cavity and pharynx (SIR: 16.54), esophagus (SIR: 10.02), and larynx (SIR: 10.34). Also, the highest SIRs following AC cases were observed in the esophagus (SIR: 8.81), stomach (SIR: 9.29), and small intestine (SIR: 4.95). SIRs for the oral cavity and pharynx, lung, and larynx were significantly higher among SCC survivors than AC survivors (all P<0.05). KM analysis revealed no significant difference of overall survival (OS) for multiple primary cancers, including those of the esophagus, stomach, oral cavity and pharynx, and lung among EC patients (log rank =2.04; P=0.564), except for prostate cancer (log rank =96.65; P<0.001). Multiple primary malignancy risk differed by the histological type of esophageal SSC and AC survivor. However, no significant relationship between survival and the multiple primary cancer sites, except for prostate cancer, was observed.

Polymorphisms of cancer-related genes and risk of multipleprimary malignancies involving colorectal cancer

Background/aim: This study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) of cancer-related genes and the risk of multiple primary malignancies involving colorectal cancer.Materials and methods: We collected tissue samples from 22 multiple primary cancer patients with primary colorectal cancer and performed genotyping assay for 116 SNP loci from 62 genes encoding peptides functioning in various signaling pathways using the DNA MassARRAY system. The chi-square test was used to compare the differences in base frequencies between patients and a control Chinese population from HapMap through the NCBI database.Results: No significant differences in frequencies were detected for 81 SNPs (P > 0.05), while serious frequency differences were observed for 35 SNPs from 31 genes (P < 0.05), which included ERCC6 (rs2228526), ERCC1 (rs3212986), CASP8 (rs3834129, rs3769818), and others presented. Five of these SNPs were previously reported to be associated with the pathogenesis of colorectal cancer.Conclusion: The 35 SNPs from 31 genes may be associated with the risk of multiple primary malignancies involving colorectal cancer.

Extremity soft tissue sarcoma with multiple primary malignancies – Characteristics and outcome

BackgroundUnderstanding the incidence and characteristics of multiple primary malignancies (MPM) has implications for guiding appropriate treatment and surveillance of extremity soft tissue sarcoma (STS). ObjectivesWe sought to examine the incidence of MPM in STS (MPM-STS), and compare their clinicopathologic characteristics and survival to those with STS only. Methods585 patients who underwent surgery for extremity STS were reviewed. Logistic regression analyses to identify factors contributing to the development of MPMs and a 1:2 matched case–control analysis to compare survival outcome were performed. ResultsOf the 585 patients analyzed, 34 (6%) with MPM were identified. On univariate logistic regression analysis, older age (>49 years) at STS diagnosis (p = 0.008) and histologic types of undifferentiated pleomorphic sarcoma or myxofibrosarcoma (p = 0.033) were significant. In multivariate analysis, only older age at STS diagnosis remained significant (OR = 2.5, p = 0.029). Cancer-specific survival of the MPM-STS group was significantly lower than that of the STS-only group (p = 0.031). However, there was no significant difference in STS-specific survival between the two groups (p = 0.208). ConclusionOur study suggests that MPM is not uncommon in extremity STS and older age at STS diagnosis is associated with risk of MPM. Prognosis of STS in the MPM-STS group seems similar to that of the STS-only group.

Risk of multiple primary malignancies following treatment of Hodgkin lymphoma

AbstractWe assessed risk, localization, and timing of third malignancies in Hodgkin lymphoma (HL) survivors. In a cohort of 3122 5-year HL survivors diagnosed before the age of 51 years and treated between 1965 and 1995, we examined whether risk factors for second and third malignancies differ and whether the occurrence of a second malignancy affects the risk of subsequent malignancies, using recurrent event analyses. After a median follow-up of 22.6 years, 832 patients developed a second malignancy and 126 patients a third one. The risk of a second malignancy was 4.7-fold increased (95% confidence interval [CI], 4.4-5.1) compared with risk in the general population; the risk for a third malignancy after a second malignancy was 5.4-fold (95% CI, 4.4-6.5) increased. The 10-year cumulative incidence of any third malignancy was 13.3%. Compared with patients still free of a second malignancy, patients with a second malignancy had a higher risk of developing subsequent malignancies. This risk depended on age, with hazard ratios of 2.2, 1.6, and 1.1 for patients aged <25, 25 to 34, and 35 to 50 years at HL treatment, respectively. In HL survivors who had a second malignancy, treating physicians should be aware of the increased risk of subsequent malignancies.

The Risk of Multiple Primary Malignancies with Colorectal Carcinoma

With advances in diagnostic techniques and treatment modalities, the number of patients identified with colorectal carcinoma who develop multiple primary malignancy during long-term follow-up has been increasing. We investigated multiple primary malignancies occurring in a large number of colorectal carcinoma patients who had undergone surgery in the 1980s at our institution. A total of 1,304 Japanese patients with colorectal carcinoma treated between January 1980 and December 1989 were prospectively followed to investigate the situations in which multiple primary malignancies occurred. To determine whether the incidence of multiple primary malignancies in this series was higher than expected, we calculated the expected numbers of carcinoma occurrences and evaluated these findings by exact binomial test. The median follow-up period was 95 months. The incidence of multiple primary malignancy was 18.7 percent (143/765) among males and 14.7 percent (79/539) among females. The most common site of multiple primary malignancy among males was the stomach, followed by the lung, prostate, larynx, liver, esophagus, and urinary bladder. The most common site among females was the uterus, followed by the stomach, breast, and liver. The sites that showed a higher incidence of multiple primary malignancy than the expected value were: the prostate, larynx, urinary bladder, oral cavity/pharynx and thyroid among males, and the uterus and oral cavity/pharynx among females. Fifteen to 20 percent of Japanese colorectal carcinoma patients experienced multiple primary malignancies. Postoperative long-term screening methods should be established considering the actual occurrence numbers and risk rate of multiple primary malignancies in addition to metachronous colorectal carcinoma.

Incidence of Multiple Primary Malignancies in a Cohort of Adult Patients with Soft Tissue Sarcoma

Some studies to date have suggested the development of multiple primary malignancies in patients with soft tissue sarcoma. The current study was performed to quantify the risk of development of multiple primary malignancies in adult patients with soft tissue sarcoma. A total of 406 consecutive patients who were diagnosed with soft tissue sarcoma were identified in the study analysis. The cumulative incidence of multiple malignancies was calculated by comparing Kaplan-Meier curves and log-rank tests from each histological type. A Cox proportional hazards model was used to estimate the influence on the hazard ratio (HR) of each variable. A total of 35 patients with soft tissue sarcoma (9%), having preceding (n = 15) and subsequent (n = 20) malignancies other than soft tissue sarcoma were documented. The 5- and 10-year estimated cumulative incidence of multiple primary malignancies were 7.6 and 12.3%, respectively. The hazard risk of multiple primary malignancies adjusted for potential confounding variables was significantly associated with age at diagnosis (HR = 1.51, P = 0.0019). The risk of multiple primary malignancies was also increased in patients with myxofibrosarcoma adjusted by the potential confounding variables (HR = 2.34, P = 0.048). The 5- and 10-year estimated cumulative incidence of multiple primary malignancies in patients with myxofibrosarcoma were both 16.9%. The results of our study confirm that the risk of multiple malignancies appears to be impacted by age at the time of diagnosis of the first tumor and by the histological type of myxofibrosarcoma.

Multiple primary malignancies

As the incidence and prevalence of cancer increase with age, it is reasonable to expect that the incidence and prevalence of multiple primary malignancies will increase as well. We ask here whether age is a risk factor for multiple primary malignancies and whether a special phenotype of older individual at increased risk of cancer may be identified. The main sources of information are autopsy series and tumor registries, which indicate that the prevalence and risk of multiple primary malignancies increase with age as expected, but that it is not possible to identify a particular phenotype that is at increased risk of multiple primary malignancies, among older individuals. It is also noted that the risk of endometrial cancer in association with breast cancer seems to increase in women aged 70 and older. Our conclusions are affected by the limitation of the sources themselves. These include for autopsy studies referral bias and overestimate of risk due to occult neoplasms, and for tumor registries, the quality and comprehensiveness of the registry and the evolution of diagnostic techniques overtime. Prospective follow-up of older cancer patients, involving measurement of circulating cytokines, whose concentration increases with age, and study of the genotype of older individuals, may provide new information about whether certain older individuals are at increased risk for multiple primary neoplasms.

Microsatellite instability as biomarker for risk of multiple primary malignancies of the upper aerodigestive tract.

Head and neck cancer (HNC) patients are at high risk of developing second primary tumors of the upper aerodigestive tract and this is a chief cause of death. Genomic instability reflecting the propensity and the susceptibility of the genome to acquire multiple alterations is considered a driving force behind multiple carcinogenesis and the alterations of the length of single repetitive genomic sequences or microsatellite instability (MI), implicating impaired DNA repair mechanisms, and could be a sensitive marker for assessing genomic instability in multiple HNC. To investigate whether a genetic defect(s) involving the mismatch repair system constitutes a risk factor in patients with multiple head and neck cancer, we examined replication errors (RER) at 10 microsatellite loci in 21 primary and 5 second primary cancers in 21 patients with multiple malignancies of the upper aerodigestive tract, in comparison with match-paired primary HNC from patients without multiple malignancies. A RER+ phenotype (alterations at > or =2 loci) was observed at 10 microsatellite alterations on chromosomes 2, 3, 11, 17 in at least one tumor from 15 out of 21 (71.5%) patients with multiple primary cancers but only in 11 tumors from 40 (27.5%) HNC patients with single cancer (P=0.001). A RER+ phenotype was also associated with a positive familial cancer history (P=0.046). Our results suggest that a genetic instability may play an important role in the pathogenesis of multiple primary cancers and that testing for MI in a primary HNC may be useful in detecting patients with high risk for developing multiple malignancies of the upper aerodigestive tract.

P53 expression: a potential biomarker for risk of multiple primary malignancies in the upper aerodigestive tract.

The concept of field cancerisation assumes that in head and neck cancer patients (HNCP) with multiple malignancies the second primary cancers may arise independently from the entire upper aerodigestive tract as a consequence of massive exposure to common carcinogens. Since mutations and/or overexpression of the p53 tumour suppressor gene represent a genetic alteration frequently occurring in HNCP, we analysed immunocytochemically p53 oncoprotein expression in first primary, second primary cancers and in macroscopically uninvolved normal epithelium from different sites of the upper aerodigestive tract from 12 HNCP with multiple malignancies, in comparison with p53 expression in biopsy specimens of the upper aerodigestive tract from 5 non-neoplastic heavy smokers, as controls. In patients with multiple malignancies 6 cases (50%) showed positive staining of both first and second primaries, whereas 3 (25%) had positive labelling of first primary cancer but not of the subsequent second primary, 2 (17%) patients showed p53 expression only in the second primary cancer, and finally only 1 patient (8%) showed no p53 immunoreactivity in both first and second primary tumours. Moreover, 10 out of 12 (83%) HNCP with multiple cancers showed p53-positive staining in the normal epithelium from different sites of the upper aerodigestive tract, also at a significant distance from the site of first and second primary malignancies. contrast, sporadic p53 immunostaining was observed only in three out of 35 (8.5%) specimens from non-neoplastic controls. In addition, in 4 HNCP with multiple tumours the histological examination of apparently normal epithelium from the upper aerodigestive tract revealed signs of moderate or severe dysplasia, and in 1 case an in situ carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Mutagen Sensitivity in Patients With Head and Neck Cancers: A Biologic Marker for Risk of Multiple Primary Malignancies

Eighty-four patients with head and neck cancers were evaluated for in vitro sensitivity to mutagens and then followed longitudinally for development of multiple primary malignancies. We assessed mutagen sensitivity by exposing lymphocytes to bleomycin in vitro and quantitating the bleomycin-induced chromosomal breaks per cell. The mutagen-hypersensitive patients, ie, those who expressed greater than 1.0 break per cell, were significantly more likely to develop multiple primary cancers than were patients who were less sensitive (less than or equal to 1.0 break per cell) (relative risk = 4.4; 95% confidence limits = 1.2, 15.8). This relationship was independent of age, sex, site, and treatment of first primary cancer and tobacco or alcohol exposures. Sensitivity to bleomycin-induced chromosomal damage serves as an indicator of genetic susceptibility to multiple primary malignancies in patients with head and neck cancers.