Bayesian Semiparametric Estimation of Cancer-Specific Age-at-Onset Penetrance With Application to Li-Fraumeni Syndrome

<p>Penetrance, which plays a key role in genetic research, is defined as the proportion of individuals with the genetic variants (i.e., genotype) that cause a particular trait and who have clinical symptoms of the trait (i.e., phenotype). We propose a Bayesian semiparametric approach to estimate the cancer-specific age-at-onset penetrance in the presence of the competing risk of multiple cancers. We employ a Bayesian semiparametric competing risk model to model the duration until individuals in a high-risk group develop different cancers, and accommodate family data using family-wise likelihoods. We tackle the ascertainment bias arising when family data are collected through probands in a high-risk population in which disease cases are more likely to be observed. We apply the proposed method to a cohort of 186 families with Li-Fraumeni syndrome identified through probands with sarcoma treated at MD Anderson Cancer Center from 1944 to 1982. Supplementary materials for this article are available online.</p

Characteristics of three patient populations used to define MDM2 SNP309 as a modifier of tumorgenisis in p53-mutation carriers.

<p>Characteristics of three patient populations used to define MDM2 SNP309 as a modifier of tumorgenisis in p53-mutation carriers.</p

The G-Allele of SNP309 Associates with an Accelerated Age of Diagnosis of Non-Gender Specific Tumors in Female but not in Male p53 Mutation Carriers.

<p>(A) The bar graph depicts the bits of mutual information between the MDM2 SNP309 locus and the age of tumor onset in females and in males. The associated p-values are depicted below. The MDM2 SNP309 locus and the age of tumor diagnosis share significant mutual information only in females and not in males. Statistical significance is represented by the black labeling of the bar graph and the p-values depicted below. The cumulative incidence of all non-gender specific tumor types for both the individuals T/T in genotype (black squares) and T/G or G/G in genotype (grey diamonds) is plotted as a function of age for females (B) and males (C). A square or a diamond represents at least one individual.</p

The effect of the MDM2 SNP309 locus and gender on the age of diagnosis in p53 mutation carriers.

<p>The effect of the MDM2 SNP309 locus and gender on the age of diagnosis in p53 mutation carriers.</p

An information-theoretic analysis reveals a significant level of mutual information between the MDM2 SNP309 locus, but not gender, and the age of tumor onset.

<p>In order to compare the age dependent incidence of cancer between males and females, individuals who developed primarily gender-specific cancers were excluded from this analysis, leaving STS, osteosarcomas and leukemmias as the major tumor types analyzed as depicted in the pie charts for both males (A) and females (B). (C) The bar graph depicts the bits of mutual information between the MDM2 SNP309 locus and the age of tumor onset, gender and the age of tumor onset and lastly between all three variables. The associated p-values are depicted below. (D) The cumulative incidence of tumor diagnosis for both the individuals T/T in genotype (black squares) and T/G or G/G (SNP309) in genotype (grey diamonds) is plotted as a function of age. A square or a diamond represents at least one individual. (E) The cumulative incidence of tumor diagnosis for both males (black squares) and females (grey diamonds) is plotted as a function of age.</p

Characterization of Genomic Alterations in Radiation-Associated Breast Cancer among Childhood Cancer Survivors, Using Comparative Genomic Hybridization (CGH) Arrays

<div><p>Ionizing radiation is an established risk factor for breast cancer. Epidemiologic studies of radiation-exposed cohorts have been primarily descriptive; molecular events responsible for the development of radiation-associated breast cancer have not been elucidated. In this study, we used array comparative genomic hybridization (array-CGH) to characterize genome-wide copy number changes in breast tumors collected in the Childhood Cancer Survivor Study (CCSS). Array-CGH data were obtained from 32 cases who developed a second primary breast cancer following chest irradiation at early ages for the treatment of their first cancers, mostly Hodgkin lymphoma. The majority of these cases developed breast cancer before age 45 (91%, n = 29), had invasive ductal tumors (81%, n = 26), estrogen receptor (ER)-positive staining (68%, n = 19 out of 28), and high proliferation as indicated by high Ki-67 staining (77%, n = 17 out of 22). Genomic regions with low-copy number gains and losses and high-level amplifications were similar to what has been reported in sporadic breast tumors, however, the frequency of amplifications of the 17q12 region containing human epidermal growth factor receptor 2 (HER2) was much higher among CCSS cases (38%, n = 12). Our findings suggest that second primary breast cancers in CCSS were enriched for an “amplifier” genomic subgroup with highly proliferative breast tumors. Future investigation in a larger irradiated cohort will be needed to confirm our findings.</p></div

Patient characteristics and treatment of CCSS cases included in this study.

<p>Abbreviations: HL = Hodgkin lymphoma, NHL = non-Hodgkin lymphoma, RT = radiotherapy, UNK = unknown.</p><p>^a0 = no direct treatment to the chest, UNK = unknown dose, >0 and < 70 Gy = direct treatment to the chest, SL = (low scatter) patient had RT, but not to the chest or an adjacent body region, SH = (high scatter) patient had RT that included arm, neck or abdomen but not chest.</p><p>Patient characteristics and treatment of CCSS cases included in this study.</p

Breast tumor characteristics of CCSS cases included in this study.

<p>Abbreviations: BC = breast cancer, DCIS = ductal cell in situ, ER = estrogen receptor, ND = not determined, UNK = unknown.</p><p>^aGrade: low = well differentiated or grade I, intermediate = moderately differentiated or grade II, high = poorly differentiated or grade III.</p><p>Breast tumor characteristics of CCSS cases included in this study.</p