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Volume 12, Issue 4

1 April 2022

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Somatic mosaicism, where two or more cell populations have different genotypes, can occur in normal cells as they undergo mutagenesis over an individual's life span. These mosaic variants can arise early in embryogenesis and be present in adult tissues. Mosaicism in cancer susceptibility genes has been observed in individuals with clinical features of hereditary predisposition syndromes, but the contribution of these mosaic variants to the development of apparently sporadic cancers has yet to be defined. Pareja, Ptashkin, Brown, and colleagues analyzed paired tumor/blood sequencing data from over 35,000 unselected patients with cancer and showed that mosaic variants affecting cancer susceptibility genes can occur early in embryogenesis and are likely to contribute to tumorigenesis, thereby increasing the risk for developing cancer. The detection of these variants may ultimately influence clinical decisions as well as preventive measures for patients and their offspring. For more information, see the article by Pareja, Ptashkin, Brown, and colleagues on page 949.
Table of Contents
Editorial Board

ISSN 2159-8274

EISSN 2159-8290

Issue Sections

In This Issue
In the Spotlight
In Focus
Reviews
Research Briefs
Research Articles
News in Brief
Research Watch

In This Issue

Extract

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In the Spotlight

Think Globally, Act Locally: Globalizing Precision Oncology

Justin T. Moyers; Vivek Subbiah

Abstract

View articletitled, Think Globally, Act Locally: Globalizing Precision Oncology

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Patchwork Cancer Predisposition

L. Alexander Liggett; Vijay G. Sankaran

Abstract

View articletitled, Patchwork Cancer Predisposition

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Vive la Résistance: T-cell Immunity in the Protection against SARS-CoV-2 Infection

Lisa H.F. McGary; Santosha A. Vardhana

Abstract

View articletitled, Vive la Résistance: T-cell Immunity in the Protection against SARS-CoV-2 Infection

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In Focus

RAS at 40: Update from the RAS Initiative

Dwight V. Nissley; Frank McCormick

Abstract

View articletitled, RAS at 40: Update from the RAS Initiative

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Reviews

A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation

Dhirendra K. Simanshu; Deborah K. Morrison

Abstract

View articletitled, A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation

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Classification of KRAS-Activating Mutations and the Implications for Therapeutic Intervention

Christian Johnson; Deborah L. Burkhart; Kevin M. Haigis

Abstract

View articletitled, Classification of KRAS-Activating Mutations and the Implications for Therapeutic Intervention

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Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants

Marco H. Hofmann; Daniel Gerlach; Sandra Misale; Mark Petronczki; Norbert Kraut

Abstract

View articletitled, Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants

Supplementary data

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Research Briefs

Genomic Landscape and Clinical Utility in Korean Advanced Pan-Cancer Patients from Prospective Clinical Sequencing: K-MASTER Program

Kyong Hwa Park; Jung Yoon Choi; Ah-Reum Lim; Ju Won Kim; Yoon Ji Choi; Soohyeon Lee; Jae Sook Sung; Hee-Joon Chung; Byunghyun Jang; Dayoung Yoon; Sukwon Kim; Jason K. Sa; Yeul Hong Kim

Abstracts

View articletitled, Genomic Landscape and Clinical Utility in Korean Advanced Pan-Cancer Patients from Prospective Clinical Sequencing: K-MASTER Program

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Cancer-Causative Mutations Occurring in Early Embryogenesis

Fresia Pareja; Ryan N. Ptashkin; David N. Brown; Fatemeh Derakhshan; Pier Selenica; Edaise M. da Silva; Andrea M. Gazzo; Arnaud Da Cruz Paula; Kelsey Breen; Ronglai Shen; Antonio Marra; Ahmet Zehir; Ryma Benayed; Michael F. Berger; Ozge Ceyhan-Birsoy; Sowmya Jairam; Margaret Sheehan; Utsav Patel; Yelena Kemel; Jacklyn Casanova-Murphy; Christopher J. Schwartz; Mahsa Vahdatinia; Elizabeth Comen; Laetitia Borsu; Xin Pei; Nadeem Riaz; David H. Abramson; Britta Weigelt; Michael F. Walsh; Anna-Katerina Hadjantonakis; Marc Ladanyi; Kenneth Offit; Zsofia K. Stadler; Mark E. Robson; Jorge S. Reis-Filho; Diana Mandelker

Abstracts

View articletitled, Cancer-Causative Mutations Occurring in Early Embryogenesis

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Research Articles

The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals

Jean-Eudes Fahrner; Imran Lahmar; Anne-Gaëlle Goubet; Yacine Haddad; Agathe Carrier; Marine Mazzenga; Damien Drubay; Carolina Alves Costa Silva; Lyon COVID Study Group; Eric de Sousa; Cassandra Thelemaque; Cléa Melenotte; Agathe Dubuisson; Arthur Geraud; Gladys Ferrere; Roxanne Birebent; Camille Bigenwald; Marion Picard; Luigi Cerbone; Joana R. Lérias; Ariane Laparra; Alice Bernard-Tessier; Benoît Kloeckner; Marianne Gazzano; François-Xavier Danlos; Safae Terrisse; Eugenie Pizzato; Caroline Flament; Pierre Ly; Eric Tartour; Nadine Benhamouda; Lydia Meziani; Abdelhakim Ahmed-Belkacem; Makoto Miyara; Guy Gorochov; Fabrice Barlesi; Alexandre Trubert; Benjamin Ungar; Yeriel Estrada; Caroline Pradon; Emmanuelle Gallois; Fanny Pommeret; Emeline Colomba; Pernelle Lavaud; Marc Deloger; Nathalie Droin; Eric Deutsch; Bertrand Gachot; Jean-Philippe Spano; Mansouria Merad; Florian Scotté; Aurélien Marabelle; Frank Griscelli; Jean-Yves Blay; Jean-Charles Soria; Miriam Merad; Fabrice André; Juliette Villemonteix; Mathieu F. Chevalier; Sophie Caillat-Zucman; Florence Fenollar; Emma Guttman-Yassky; Odile Launay; Guido Kroemer; Bernard La Scola; Markus Maeurer; Lisa Derosa; Laurence Zitvogel

In both healthy and cancer-bearing individuals, Th1/Tc1 response of spike protein–specific memory T cells is associated with susceptibility to SARS-CoV-2 infection.

Abstract

View articletitled, The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals

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Early Tumor–Immune Microenvironmental Remodeling and Response to First-Line Fluoropyrimidine and Platinum Chemotherapy in Advanced Gastric Cancer

Ryul Kim; Minae An; Hyuk Lee; Arnav Mehta; You Jeong Heo; Kyoung-Mee Kim; Song-Yi Lee; Jeonghyeon Moon; Seung Tae Kim; Byung-Hoon Min; Tae Jun Kim; Sun Young Rha; Won Ki Kang; Woong-Yang Park; Samuel J. Klempner; Jeeyun Lee

Abstracts

View articletitled, Early Tumor–Immune Microenvironmental Remodeling and Response to First-Line Fluoropyrimidine and Platinum Chemotherapy in Advanced Gastric Cancer

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Targeting S100A9–ALDH1A1–Retinoic Acid Signaling to Suppress Brain Relapse in EGFR-Mutant Lung Cancer

Anup Kumar Biswas; Seoyoung Han; Yifan Tai; Wanchao Ma; Courtney Coker; S. Aidan Quinn; Ahmad Rushdi Shakri; Timothy James Zhong; Hanna Scholze; Galina G. Lagos; Angeliki Mela; Katia Manova-Todorova; Elisa de Stanchina; Adolfo A. Ferrando; Cathy Mendelsohn; Peter Canoll; Helena A. Yu; Paul K. Paik; Anjali Saqi; Catherine A. Shu; Mark G. Kris; Joan Massague; Swarnali Acharyya

The S100A9–ALDH1A1–retinoic acid signaling pathway mediates osimertinib resistance and brain relapse in models of EGFR-mutant lung cancer.

Abstract

View articletitled, Targeting S100A9–ALDH1A1–Retinoic Acid Signaling to Suppress Brain Relapse in EGFR-Mutant Lung Cancer

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Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2⁺ Breast Cancer

Chewei Anderson Chang; Jayu Jen; Shaowen Jiang; Azin Sayad; Arvind Singh Mer; Kevin R. Brown; Allison M.L. Nixon; Avantika Dhabaria; Kwan Ho Tang; David Venet; Christos Sotiriou; Jiehui Deng; Kwok-kin Wong; Sylvia Adams; Peter Meyn; Adriana Heguy; Jane A. Skok; Aristotelis Tsirigos; Beatrix Ueberheide; Jason Moffat; Abhyudai Singh; Benjamin Haibe-Kains; Alireza Khodadadi-Jamayran; Benjamin G. Neel

Abstracts

View articletitled, Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

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Plasticity of Extrachromosomal and Intrachromosomal BRAF Amplifications in Overcoming Targeted Therapy Dosage Challenges

Kai Song; Jenna K. Minami; Arthur Huang; Siavash R. Dehkordi; Shirley H. Lomeli; Jens Luebeck; Mark H. Goodman; Gatien Moriceau; Oscar Krijgsman; Prashanthi Dharanipragada; Trevor Ridgley; William P. Crosson; Jesus Salazar; Eli Pazol; Gabriel Karin; Rachana Jayaraman; Nikolas G. Balanis; Salwan Alhani; Kyle Sheu; Johanna ten Hoeve; Amelia Palermo; Stephen E. Motika; T. Niroshi Senaratne; Kim H. Paraiso; Paul J. Hergenrother; P. Nagesh Rao; Asha S. Multani; Daniel S. Peeper; Vineet Bafna; Roger S. Lo; Thomas G. Graeber

Abstracts

View articletitled, Plasticity of Extrachromosomal and Intrachromosomal BRAF Amplifications in Overcoming Targeted Therapy Dosage Challenges

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A Natural Polyphenol Exerts Antitumor Activity and Circumvents Anti–PD-1 Resistance through Effects on the Gut Microbiota

Meriem Messaoudene; Reilly Pidgeon; Corentin Richard; Mayra Ponce; Khoudia Diop; Myriam Benlaifaoui; Alexis Nolin-Lapalme; Florent Cauchois; Julie Malo; Wiam Belkaid; Stephane Isnard; Yves Fradet; Lharbi Dridi; Dominique Velin; Paul Oster; Didier Raoult; François Ghiringhelli; Romain Boidot; Sandy Chevrier; David T. Kysela; Yves V. Brun; Emilia Liana Falcone; Geneviève Pilon; Florian Plaza Oñate; Oscar Gitton-Quent; Emmanuelle Le Chatelier; Sylvere Durand; Guido Kroemer; Arielle Elkrief; André Marette; Bastien Castagner; Bertrand Routy

The polyphenol castalagin acts as a prebiotic and exerts antitumor activity as well as potentiates anti–PD-1 immune efficacy through a beneficial shift in microbiome composition.

Abstract

View articletitled, A Natural Polyphenol Exerts Antitumor Activity and Circumvents Anti–PD-1 Resistance through Effects on the Gut Microbiota

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Deconvolving Clinically Relevant Cellular Immune Cross-talk from Bulk Gene Expression Using CODEFACS and LIRICS Stratifies Patients with Melanoma to Anti–PD-1 Therapy

Kun Wang; Sushant Patkar; Joo Sang Lee; E. Michael Gertz; Welles Robinson; Fiorella Schischlik; David R. Crawford; Alejandro A. Schäffer; Eytan Ruppin

Abstracts

View articletitled, Deconvolving Clinically Relevant Cellular Immune Cross-talk from Bulk Gene Expression Using CODEFACS and LIRICS Stratifies Patients with Melanoma to Anti–PD-1 Therapy

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Subversion of Serotonin Receptor Signaling in Osteoblasts by Kynurenine Drives Acute Myeloid Leukemia

Marta Galán-Díez; Florence Borot; Abdullah Mahmood Ali; Junfei Zhao; Eva Gil-Iturbe; Xiaochuan Shan; Na Luo; Yongfeng Liu; Xi-Ping Huang; Brygida Bisikirska; Rossella Labella; Irwin Kurland; Bryan L. Roth; Matthias Quick; Siddhartha Mukherjee; Raul Rabadán; Martin Carroll; Azra Raza; Stavroula Kousteni

Kynurenine secreted by acute myeloid leukemia cells activates the serotonin receptor 1b in osteoblasts to drive leukemia through the acute-phase protein serum amyloid A (SAA), with an increase in both kynurenine and SAA seen in mouse models and patient samples.

Abstract

View articletitled, Subversion of Serotonin Receptor Signaling in Osteoblasts by Kynurenine Drives Acute Myeloid Leukemia

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Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis

Satoru Yonekura; Safae Terrisse; Carolina Alves Costa Silva; Antoine Lafarge; Valerio Iebba; Gladys Ferrere; Anne-Gaëlle Goubet; Jean-Eudes Fahrner; Imran Lahmar; Kousuke Ueda; Gibrail Mansouri; Eugénie Pizzato; Pierre Ly; Marine Mazzenga; Cassandra Thelemaque; Marine Fidelle; Fanny Jaulin; Jérôme Cartry; Marc Deloger; Marine Aglave; Nathalie Droin; Paule Opolon; Angélique Puget; Fanny Mann; Michel Neunlist; Anne Bessard; Laetitia Aymeric; Tamara Matysiak-Budnik; Jacques Bosq; Paul Hofman; Connie P.M. Duong; Sophie Ugolini; Valentin Quiniou; Sylvie Berrard; Bernhard Ryffel; Oliver Kepp; Guido Kroemer; Bertrand Routy; Leonardo Lordello; Mohamed-Amine Bani; Nicola Segata; Fjodor Yousef Yengej; Hans Clevers; Jean-Yves Scoazec; Edoardo Pasolli; Lisa Derosa; Laurence Zitvogel

Abstracts

View articletitled, Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis

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Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation

Bappaditya Chandra; Nicole L. Michmerhuizen; Hazheen K. Shirnekhi; Swarnendu Tripathi; Brittany J. Pioso; David W. Baggett; Diana M. Mitrea; Ilaria Iacobucci; Michael R. White; Jingjing Chen; Cheon-Gil Park; Huiyun Wu; Stanley Pounds; Anna Medyukhina; Khaled Khairy; Qingsong Gao; Chunxu Qu; Sherif Abdelhamed; Scott D. Gorman; Simranjot Bawa; Carolyn Maslanka; Swati Kinger; Priyanka Dogra; Mylene C. Ferrolino; Danika Di Giacomo; Cristina Mecucci; Jeffery M. Klco; Charles G. Mullighan; Richard W. Kriwacki

NUP98 fusion oncoproteins promote leukemogenesis by undergoing phase separation in the nuclei of hematopoietic cells to form hundreds of punctate transcriptional condensates that drive aberrant gene expression and induce myeloid transformation.

Abstract

View articletitled, Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation

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