treat cancer, monitor responses to therapy and/or determine an individual’s risk of developing cancer over their lifetime (75-77). RNA Variations Most human genes contain information for making proteins in fragments of DNA, called exons. Exons are interspersed by DNA sequences, called introns, that do not contain information necessary to make a functional protein. When a gene is transcribed into mRNA, the initial mRNA molecule contains a copy of both exons and introns. An intricate “cut and paste” process, called splicing, removes introns and joins exons together to produce an mRNA molecule that is subsequently translated into a functional protein by the cellular machinery. RNA splicing plays a pivotal role in normal cellular functions. In cancer cells, changes in proteins necessary for splicing can produce aberrant mRNA molecules, which subsequently make abnormal proteins that can fuel cancer development, lead to treatment resistance, and alter immune cell function (78). Ongoing research is focused on understanding how cancer-related changes in RNA splicing can be leveraged for therapeutic purposes (79). Researchers are also using transcriptomics—the study of all RNA molecules in a cell—to establish comprehensive patterns of the types and levels of RNA, or transcriptomes, present in healthy tissues versus tumors. Knowledge gleaned from such studies helps researchers understand how different types of RNA may contribute to cancer development. Technological breakthroughs Inherited Cancer Risk Depicted here are selected cancer types that are associated with inherited cancer syndromes. Also shown in parentheses are the genes, mutations in which are linked with various inherited cancer syndromes that predispose individuals to the shown cancer types. Developed from (1). FIGURE 5 Blood cancers (Leukemia; Lymphoma; Myelodysplastic syndrome) Ataxia telangiectasia (ATM) Inherited bone marrow failure syndromes, such as Fanconi's anemia and telomere syndromes (FANCC, FANC, FANCB, FANCS, BRCA1, TERT, TERC) Li-Fraumeni syndrome (TP53) Hereditary myeloid malignancy syndromes, such as familial MDS/Acute myeloid leukemias (RUNX1, GATA2, CEBPA, ETV6, DDX41, ANKRD26, ATG2B/GSKIP) Lung Peutz–Jeghers syndrome (STK11/LKB1) Liver Peutz–Jeghers syndrome (STK11/LKB1) Gastric MYH-associated polyposis (MUTYH) Diuse gastric and lobular breast cancer syndrome (CDH1) Colorectal Lynch syndrome (EPCAM, MLH1, MSH2, MSH6, PMS2) MYH-associated polyposis (MUTYH) Familial adenomatous polyposis (APC) Skin Familial atypical multiple mole–melanoma syndrome (CDKN2A) Familial glioma-melanoma syndrome (CDKN2A) Multiple endocrine neoplasia 1 (MEN1) Xeroderma pigmentosum (XPD, XPB, XPA) Basal cell nevus syndrome (PTCH1, PTCH2, SUFU) Uterine Hereditary leiomyomatosis and renal cell cancer (FH) Peutz–Jeghers syndrome (STK11/LKB1) Kidney von Hippel-Lindau syndrome (VHL) Wilms tumor (WT1) Pancreas Breast-ovarian cancer syndrome (BRCA1, BRCA2) Familial atypical multiple mole–melanoma syndrome (CDKN2A) Hereditary pancreatitis/familial pancreatitis (PRSS1, SPINK1) Multiple endocrine neoplasia 1 (MEN1) Peutz–Jeghers syndrome (STK11/LKB1) Breast Cowden syndrome (PTEN) Breast-ovarian cancer syndrome (BRCA1, BRCA2) Li-Fraumeni syndrome (TP53) Thyroid Multiple endocrine neoplasia 2 (RET, NTRK1) Cowden syndrome (PTEN) MYH-associated polyposis (MUTYH) Cancers of the Brain and the Nervous System Basal cell nevus syndrome (PTCH1, PTCH2, SUFU) Familial glioma-melanoma syndrome (CDKN2A) Familial adenomatous polyposis (APC) Neurofibromatosis type I and type II (NF1 and NF2) Brain tumor polyposis type I (MLH1, PMS2) Brain tumor polyposis type II (APC) von Hippel-Lindau syndrome (VHL) All cancers Bloom syndrome (BLM) Ovarian Breast-ovarian cancer syndrome (BRCA1, BRCA2) Peutz–Jeghers syndrome (STK11/LKB1) Bone Retinoblastoma predisposition syndrome (RB1) Li-Fraumeni syndrome (TP53) Eye Retinoblastoma predisposition syndrome (RB1) A1, BRCA2) ma syndrome (CDKN2A) eatitis (PRSS1, SPINK1) ) Understanding the Path to Cancer Development AACR Cancer Progress Report 2023 31
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