Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2021
Multiple Primary Cancers in Patients Undergoing Tumor-Normal Sequencing Define Novel Associations.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАКомментарийНазвание и аннотация: Перевод пока не подготовлен
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Liu Ying L, Cadoo Karen A, Mukherjee Semanti, Khurram Aliya, Tkachuk Kaitlyn, Kemel Yelena, Maio Anna, Belhadj Sami, Carlo Maria I, Latham Alicia, Walsh Michael F, Dubard-Gault Marianne E, Wang Yuhan, Brannon A Rose, Salo-Mullen Erin, Sheehan Margaret, Fiala Elise, Devolder Bryan, Dandiker Sita, Mandelker Diana, Zehir Ahmet, Ladanyi Marc, Berger Michael F, Solit David B, Bandlamudi Chaitanya, Ravichandran Vignesh, Bajorin Dean F, Stadler Zsofia K, Robson Mark E, Vijai Joseph, Seshan Venkatraman, Offit Kenneth
Аннотация
BACKGROUND: Cancer survivors are developing more subsequent tumors. We sought to characterize patients with multiple (≥2) primary cancers (MPC) to assess associations and genetic mechanisms.
METHODS: Patients were prospectively consented (01/2013-02/2019) to tumor-normal sequencing via a custom targeted panel (MSK-IMPACT). A subset consented to return of results of ≥76 cancer predisposition genes. International Agency for Research on Cancer (IARC) 2004 rules for defining MPC were applied. Tumor pairs were created to assess relationships between cancers. Age-adjusted, sex-specific, standardized incidence ratios (SIR) for first to second cancer event combinations were calculated using SEER rates, adjusting for confounders and time of ascertainment. Associations were made with germline and somatic variants.
RESULTS: Of 24,241 patients, 4,340 had MPC (18%); 20% were synchronous. Most (80%) had two primaries; however, 4% had ≥4 cancers. SIR analysis found lymphoma-lung, lymphoma-uterine, breast-brain, and melanoma-lung pairs in women and prostate-mesothelioma, prostate-sarcoma, melanoma-stomach, and prostate-brain pairs in men in excess of expected after accounting for synchronous tumors, known inherited cancer syndromes, and environmental exposures. Of 1,580 (36%) patients who received germline results, 324 (21%) had 361 pathogenic/likely pathogenic variants (PV), 159 (44%) in high penetrance genes. Of tumor samples analyzed, 55% exhibited loss of heterozygosity at the germline variant. In those with negative germline findings, melanoma, prostate, and breast cancers were common.
CONCLUSIONS: We identified tumor pairs without known predisposing mutations that merit confirmation and will require novel strategies to elucidate genetic mechanisms of shared susceptibilities.
IMPACT: If verified, patients with MPC with novel phenotypes may benefit from targeted cancer surveillance.
METHODS: Patients were prospectively consented (01/2013-02/2019) to tumor-normal sequencing via a custom targeted panel (MSK-IMPACT). A subset consented to return of results of ≥76 cancer predisposition genes. International Agency for Research on Cancer (IARC) 2004 rules for defining MPC were applied. Tumor pairs were created to assess relationships between cancers. Age-adjusted, sex-specific, standardized incidence ratios (SIR) for first to second cancer event combinations were calculated using SEER rates, adjusting for confounders and time of ascertainment. Associations were made with germline and somatic variants.
RESULTS: Of 24,241 patients, 4,340 had MPC (18%); 20% were synchronous. Most (80%) had two primaries; however, 4% had ≥4 cancers. SIR analysis found lymphoma-lung, lymphoma-uterine, breast-brain, and melanoma-lung pairs in women and prostate-mesothelioma, prostate-sarcoma, melanoma-stomach, and prostate-brain pairs in men in excess of expected after accounting for synchronous tumors, known inherited cancer syndromes, and environmental exposures. Of 1,580 (36%) patients who received germline results, 324 (21%) had 361 pathogenic/likely pathogenic variants (PV), 159 (44%) in high penetrance genes. Of tumor samples analyzed, 55% exhibited loss of heterozygosity at the germline variant. In those with negative germline findings, melanoma, prostate, and breast cancers were common.
CONCLUSIONS: We identified tumor pairs without known predisposing mutations that merit confirmation and will require novel strategies to elucidate genetic mechanisms of shared susceptibilities.
IMPACT: If verified, patients with MPC with novel phenotypes may benefit from targeted cancer surveillance.